Roles of EGFR, PI3K, AKT, and mTOR in heavy metal-induced cancer

Current Cancer Drug Targets

Volumn 13, Issue 3, 2013, Pages 252-266

  Carpenter, Richard L ^a   Jiang, Bing Hua ^a  

^a THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

AKT; Arsenic; Cadmium; Cancer; Chromium; EGFR; mTOR; Nickel; P70S6K1; PI3K

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL) IMIDAZO [4, 5 C] QUINOLIN 2 (1H, 3H) ONE; 1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 MORPHOLINO 8 PHENYLCHROMONE; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL) MORPHOLINIO] METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; APIGENIN; ARSENIC; CADMIUM; CARCINOGEN; CETUXIMAB; CHROMIUM; CURCUMIN; CYCLOOXYGENASE 2; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EPIDERMAL GROWTH FACTOR RECEPTOR 3; ERLOTINIB; GEFITINIB; HEAVY METAL; INTERLEUKIN 6; MAMMALIAN TARGET OF RAPAMYCIN; MATRIX METALLOPROTEINASE; NICKEL; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3, 4, 5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PROTEIN BCL 2; PROTEIN KINASE B; PROTEIN TYROSINE KINASE; RESVERATROL; S6 KINASE; TRANSCRIPTION FACTOR EZH2; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANGIOGENESIS; APOPTOSIS; CANCER PROGNOSIS; CANCER RISK; CARCINOGENICITY; CELL PROLIFERATION; CELL SURVIVAL; CELL TRANSFORMATION; CHEMOPROPHYLAXIS; HUMAN; NEOPLASM; NONHUMAN; OCCUPATIONAL EXPOSURE; PHASE 1 CLINICAL TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL TRANSFORMATION, NEOPLASTIC; ENZYME INHIBITORS; HUMANS; METALS, HEAVY; MOLECULAR TARGETED THERAPY; NEOPLASM PROTEINS; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASE; PROTO-ONCOGENE PROTEINS C-AKT; RECEPTOR, EPIDERMAL GROWTH FACTOR; RIBOSOMAL PROTEIN S6 KINASES, 70-KDA; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84876837765     PISSN: 15680096     EISSN: 18735576     Source Type: Journal    
DOI: 10.2174/1568009611313030004     Document Type: Review

References (236)

1. American Cancer Society. Cancer Facts & Figures 2010. Atlanta, GA, American Cancer Society. 2010.
2. American Cancer Society. Cancer Facts & Figures 2009. Atlanta, GA, American Cancer Society. 2009.
3. International Agency for Research on Cancer. Some drinking-water disinfectants and contaminants, including arsenic. IARC Monogr Eval. Carcinog. Risks Hum. 2004, 84, 1-477.
4. International Agency for Research on Cancer. Beryllium, Cadmium, Mercury, and Exposures in the Glass Manufacturing Industry. IARC Monogr. Eval. Carcinog. Risks Hum. 1993, 58, 1-444.
5. International Agency for Research on Cancer. Chromium, Nickel and Welding. IARC Monogr Eval. Carcinog. Risks Hum. 1990, 49.
6. Durham, T. R.; Snow, E. T. Metal ions and carcinogenesis. EXS 2006, 97-130.
7. Joseph, P. Mechanisms of cadmium carcinogenesis. Toxicol. Appl. Pharmacol. 2009, 238, 272-279.
8. Rossman, T. G. Mechanism of arsenic carcinogenesis: an integrated approach. Mutat. Res. 2003, 533, 37-65.
9. Zhao, J.; Shi, X.; Castranova, V.; Ding, M. Occupational toxicology of nickel and nickel compounds. J. Environ. Pathol. Toxicol. Oncol. 2009, 28, 177-208.
10. Bertolero, F.; Pozzi, G.; Sabbioni, E.; Saffiotti, U. Cellular uptake and metabolic reduction of pentavalent to trivalent arsenic as determinants of cytotoxicity and morphological transformation. Carcinogenesis 1987, 8, 803-808.
11. Boffetta, P. Epidemiology of environmental and occupational cancer. Oncogene 2004, 23, 6392-6403.
12. Environmental Protection Agency. National Primary Drinking Water Regulations; Arsenic and Clarification to Compliance and New Source Contaminants Monitoring. 66 FR 6976. 2001; Washington, D.C., Environmental Protection Agency.
13. Rahman, M. M.; Chowdhury, U. K.; Mukherjee, S. C.; Mondal, B. K.; Paul, K.; Lodh, D.; Biswas, B. K.; Chanda, C. R.; Basu, G. K.; Saha, K. C.; Roy, S.; Das, R.; Palit, S. K.; Quamruzzaman, Q.; Chakraborti, D. Chronic arsenic toxicity in Bangladesh and West Bengal, India--a review and commentary. J. Toxicol. Clin. Toxicol. 2001, 39, 683-700.
14. National Research Council. Arsenic in Drinking Water 2001 Update. National Academy Press, 2001; Washington, D.C.
15. Science Applications International Corporation. Estimated National Occurrence and Exposure to Arsenic in Public Drinking Water Supplies (Revised Draft). Prepared for U.S. EPA under Contract no. 68-01-766. 1987. Washington, D.C., Environmental Protection Agency.
16. Chen, C. J.; Chuang, Y. C.; Lin, T. M.; Wu, H. Y. Malignant neoplasms among residents of a blackfoot disease-endemic area in Taiwan: high-arsenic artesian well water and cancers. Cancer Res. 1985, 45, 5895-5899.
17. Chen, C. J.; Chuang, Y. C.; You, S. L.; Lin, T. M.; Wu, H. Y. A retrospective study on malignant neoplasms of bladder, lung and liver in blackfoot disease endemic area in Taiwan. Br. J. Cancer 1986, 53, 399-405.
18. Axelson, O.; Dahlgren, E.; Jansson, C. D.; Rehnlund, S. O. Arsenic exposure and mortality: a case-referent study from a Swedish copper smelter. Br. J. Ind. Med. 1978, 35, 8-15.
19. Enterline, P. E.; Henderson, V. L.; Marsh, G. M. Exposure to arsenic and respiratory cancer. A reanalysis. Am. J. Epidemiol. 1987, 125, 929-938.
20. Enterline, P. E.; Marsh, G. M.; Esmen, N. A.; Henderson, V. L.; Callahan, C. M.; Paik, M. Some effects of cigarette smoking, arsenic, and SO2 on mortality among US copper smelter workers. J. Occup. Med. 1987, 29, 831-838.
21. Enterline, P. E.; Day, R.; Marsh, G. M. Cancers related to exposure to arsenic at a copper smelter. Occup. Environ. Med. 1995, 52, 28-32.
22. Jarup, L.; Pershagen, G. Arsenic exposure, smoking, and lung cancer in smelter workers--a case-control study. Am. J. Epidemiol. 1991, 134, 545-551.
23. Lee, A. M.; Fraumeni, J. F. Jr. Arsenic and respiratory cancer in man: an occupational study. J. Natl. Cancer Inst. 1969, 42, 1045-1052.
24. Lee-Feldstein, A. Cumulative exposure to arsenic and its relationship to respiratory cancer among copper smelter employees. J. Occup. Med. 1986, 28, 296-302.
25. Lee-Feldstein, A. A comparison of several measures of exposure to arsenic. Matched case-control study of copper smelter employees. Am. J. Epidemiol. 1989, 129, 112-124.
26. Lubin, J. H.; Pottern, L. M.; Blot, W. J.; Tokudome, S.; Stone, B. J.; Fraumeni, J. F. Jr. Respiratory cancer among copper smelter workers: recent mortality statistics. J. Occup. Med. 1981, 23, 779-784.
27. Taylor, P. R.; Qiao, Y. L.; Schatzkin, A.; Yao, S. X.; Lubin, J.; Mao, B. L.; Rao, J. Y.; McAdams, M.; Xuan, X. Z.; Li, J. Y. Relation of arsenic exposure to lung cancer among tin miners in Yunnan Province, China. Br. J. Ind. Med. 1989, 46, 881-886.
28. Tokudome, S.; Kuratsune, M. A cohort study on mortality from cancer and other causes among workers at a metal refinery. Int. J. Cancer 1976, 17, 310-317.
29. Xu, Z. Y.; Blot, W. J.; Xiao, H. P.; Wu, A.; Feng, Y. P.; Stone, B. J.; Sun, J.; Ershow, A. G.; Henderson, B. E.; Fraumeni, J. F. Jr. Smoking, air pollution, and the high rates of lung cancer in Shenyang, China. J. Natl. Cancer Inst. 1989, 81, 1800-1806.
30. Wise, S. S.; Holmes, A. L.; Qin, Q.; Xie, H.; Katsifis, S. P.; Thompson, W. D.; Wise, J. P. Sr. Comparative genotoxicity and cytotoxicity of four hexavalent chromium compounds in human bronchial cells. Chem. Res. Toxicol. 2010, 23, 365-372.
31. Franchini, I.; Magnani, F.; Mutti, A. Mortality experience among chromeplating workers. Initial findings. Scand. J. Work Environ. Health 1983, 9, 247-252.
32. Hansen, K. S.; Lauritsen, J. M.; Skytthe, A. Cancer incidence among mild steel and stainless steel welders and other metal workers. Am. J. Ind. Med. 1996, 30, 373-382.
33. Alderson, M. R.; Rattan, N. S.; Bidstrup, L. Health of workmen in the chromate-producing industry in Britain. Br. J. Ind. Med. 1981, 38, 117-124.
34. Langard, S.; Vigander, T. Occurrence of lung cancer in workers producing chromium pigments. Br. J. Ind. Med. 1983, 40, 71-74.
35. Hayes, R. B.; Lilienfeld, A. M.; Snell, L. M. Mortality in chromium chemical production workers: a prospective study. Int. J. Epidemiol. 1979, 8, 365-374.
36. Pastides, H.; Austin, R.; Lemeshow, S.; Klar, J.; Mundt, K. A. A retrospective-cohort study of occupational exposure to hexavalent chromium. Am. J. Ind. Med. 1994, 25, 663-675.
37. International Agency for Research on Cancer. Overall evaluations of carcinogenicity: an updating of IARC Monographs volumes 1 to 42. IARC Monogr. Eval. Carcinog. Risks Hum. Suppl, 1987, 7, 1-440.
38. Holmes, A. L.; Wise, S. S.; Sandwick, S. J.; Wise, J. P. Sr. The clastogenic effects of chronic exposure to particulate and soluble Cr(VI) in human lung cells. Mutat. Res. 2006, 610, 8-13.
39. Wise, S. S.; Holmes, A. L.; Wise, J. P. Sr. Particulate and soluble hexavalent chromium are cytotoxic and genotoxic to human lung epithelial cells. Mutat. Res. 2006, 610, 2-7.
40. Birk, T.; Mundt, K. A.; Dell, L. D.; Luippold, R. S.; Miksche, L.; Steinmann-Steiner-Haldenstaett, W., Mundt, D. J. Lung cancer mortality in the German chromate industry, 1958 to 1998. J. Occup. Environ. Med. 2006, 48, 426-433.
41. Davies, J. M.; Easton, D. F.; Bidstrup, P. L. Mortality from respiratory cancer and other causes in United Kingdom chromate production workers. Br. J. Ind. Med. 1991, 48, 299-313.
42. Deschamps, F.; Moulin, J. J.; Wild, P.; Labriffe, H.; Haguenoer, J. M. Mortality study among workers producing chromate pigments in France. Int. Arch. Occup. Environ. Health, 1995, 67, 147-152.
43. Fryzek, J. P.; Mumma, M. T.; McLaughlin, J. K.; Henderson, B. E.; Blot, W. J. Cancer mortality in relation to environmental chromium exposure. J. Occup. Environ. Med. 2001, 43, 635-640.
44. Gibb, H. J.; Lees, P. S.; Pinsky, P. F.; Rooney, B. C. Lung cancer among workers in chromium chemical production. Am. J. Ind. Med. 2000, 38, 115-126.
45. Horiguchi, S.; Morinaga, K.; Endo, G. Epidemiological study of mortality from cancer among chromium platers. Asia Pac. J. Public Health 1990, 4, 169-174.
46. Kano, K.; Horikawa, M.; Utsunomiya, T.; Tati, M.; Satoh, K.; Yamaguchi, S. Lung cancer mortality among a cohort of male chromate pigment workers in Japan. Int. J. Epidemiol. 1993, 22, 16-22.
47. Korallus, U.; Ulm, K.; Steinmann-Steiner-Haldenstaett, W. Bronchial carcinoma mortality in the German chromate-producing industry: the effects of process modification. Int. Arch. Occup. Environ. Health 1993, 65, 171-178.
48. Luippold, R. S.; Mundt, K. A.; Austin, R. P.; Liebig, E.; Panko, J.; Crump, C.; Crump, K.; Proctor, D. Lung cancer mortality among chromate production workers. Occup. Environ. Med. 2003, 60, 451-457.
49. Luippold, R. S.; Mundt, K. A.; Dell, L. D.; Birk, T. Low-level hexavalent chromium exposure and rate of mortality among US chromate production employees. J. Occup. Environ. Med. 2005, 47, 381-385.
50. Sorahan, T.; Harrington, J. M. Lung cancer in Yorkshire chrome platers, 1972-97. Occup. Environ. Med. 2000, 57, 385-389.
51. Sorahan, T.; Burges, D. C.; Hamilton, L.; Harrington, J. M. Lung cancer mortality in nickel/chromium platers, 1946-95. Occup. Environ. Med. 1998, 55, 236-242.
52. Stern, F. B. Mortality among chrome leather tannery workers: an update. Am. J. Ind. Med. 2003, 44, 197-206.
53. Doll, R.; Andersen, A.; Cooper, W. C. Report of the International Committee on Nickel Carcinogenesis in Man. Scand. J. Work Environ. Health 1990, 16, 1-82.
54. Andersen, A.; Berge, S. R.; Engeland, A.; Norseth, T. Exposure to nickel compounds and smoking in relation to incidence of lung and nasal cancer among nickel refinery workers. Occup. Environ. Med. 1996, 53, 708-713.
55. Diwan, B. A.; Kasprzak, K. S.; Rice, J. M. Transplacental carcinogenic effects of nickel(II) acetate in the renal cortex, renal pelvis and adenohypophysis in F344/NCr rats. Carcinogenesis 1992, 13, 1351-1357.
56. Dunnick, J. K.; Elwell, M. R.; Radovsky, A. E.; Benson, J. M.; Hahn, F. F.; Nikula, K. J.; Barr, E.B.; Hobbs, C. H. Comparative carcinogenic effects of nickel subsulfide, nickel oxide, or nickel sulfate hexahydrate chronic exposures in the lung. Cancer Res. 1995, 55, 5251-5256.
57. Kasprzak, K. S.; Diwan, B. A.; Konishi, N.; Misra, M.; Rice, J. M. Initiation by nickel acetate and promotion by sodium barbital of renal cortical epithelial tumors in male F344 rats. Carcinogenesis 1990, 11, 647-652.
58. Sorahan, T.; Waterhouse, J. A. Mortality study of nickel-cadmium battery workers by the method of regression models in life tables. Br. J. Ind. Med. 1983, 40, 293-300.
59. Anttila, A.; Pukkala, E.; Aitio, A.; Rantanen, T.; Karjalainen, S. Update of cancer incidence among workers at a copper/nickel smelter and nickel refinery. Int. Arch. Occup. Environ. Health 1998, 71, 245-250.
60. Grimsrud, T. K.; Berge, S. R.; Haldorsen, T.; Andersen, A. Can lung cancer risk among nickel refinery workers be explained by occupational exposures other than nickel? Epidemiology 2005, 16, 146-154.
61. Grimsrud, T. K.; Berge, S. R.; Martinsen, J. I.; Andersen, A. Lung cancer incidence among Norwegian nickel-refinery workers 1953-2000. J. Environ. Monit. 2003, 5, 190-197.
62. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Cadmium. TP-92/06. 1993. Atlanta, GA, US Department of Health and Human Services.
63. Satarug, S.; Baker, R.; Urbenjapol, S.; Haswell-Elkins, M.; Reilly, P. E.; Williams, D. J.; Moore, M. R. A global perspective on cadmium pollution and toxicity in non-occupationally exposed population. Toxicol. Lett. 2003, 137, 65-83.
64. Thun, M. J.; Elinder, C. G.; Friberg, L. Scientific basis for an occupational standard for cadmium. Am. J. Ind. Med. 1991, 20, 629-642.
65. Jin, T.; Lu, J.; Nordberg, M. Toxicokinetics and biochemistry of cadmium with special emphasis on the role of metallothionein. Neurotoxicology 1998, 19, 529-535.
66. Kazantzis, G.; Lam, T. H.; Sullivan, K. R. Mortality of cadmiumexposed workers. A five-year update. Scand. J. Work Environ. Health 1988, 14, 220-223.
67. Antila, E.; Mussalo-Rauhamaa, H.; Kantola, M.; Atroshi, F.; Westermarck, T. Association of cadmium with human breast cancer. Sci. Total Environ. 1996, 186, 251-256.
68. Armstrong, B. G.; Kazantzis, G. Prostatic cancer and chronic respiratory and renal disease in British cadmium workers: a case control study. Br. J. Ind. Med. 1985, 42, 540-545.
69. Elinder, C. G.; Kjellstrom, T.; Hogstedt, C.; Andersson, K.; Spang, G. Cancer mortality of cadmium workers. Br. J. Ind. Med. 1985, 42, 651-655.
70. Hu, J.; Mao, Y.; White, K. Renal cell carcinoma and occupational exposure to chemicals in Canada. Occup. Med.(Lond) 2002, 52, 157-164.
71. Kolonel, L. N. Association of cadmium with renal cancer. Cancer 1976, 37, 1782-1787.
72. Mandel, J. S.; McLaughlin, J. K.; Schlehofer, B.; Mellemgaard, A.; Helmert, U.; Lindblad, P.; McCredie, M.; Adami, H. O. International renal-cell cancer study. IV. Occupation. Int. J. Cancer 1995, 61, 601-605.
73. McElroy, J. A.; Shafer, M. M.; Trentham-Dietz, A.; Hampton, J. M.; Newcomb, P. A. Cadmium exposure and breast cancer risk. J. Natl. Cancer Inst. 2006, 98, 869-873.
74. Pesch, B.; Haerting, J;, Ranft, U.; Klimpel, A.; Oelschlagel, B.; Schill, W. Occupational risk factors for renal cell carcinoma: agentspecific results from a case-control study in Germany. MURC Study Group. Multicenter urothelial and renal cancer study. Int. J. Epidemiol. 2000, 29, 1014-1024.
75. Schwartz, G. G.; Reis, I. M. Is cadmium a cause of human pancreatic cancer? Cancer Epidemiol. Biomarkers Prev. 2000, 9, 139-145.
76. Jarup, L.; Bellander, T.; Hogstedt, C.; Spang, G. Mortality and cancer incidence in Swedish battery workers exposed to cadmium and nickel. Occup. Environ. Med., 1998, 55, 755-759.
77. Kjellstrom, T.; Friberg, L.; Rahnster, B. Mortality and cancer morbidity among cadmium-exposed workers. Environ. Health Perspect. 1979, 28, 199-204.
78. Sorahan, T.; Lancashire, R. J. Lung cancer mortality in a cohort of workers employed at a cadmium recovery plant in the United States: an analysis with detailed job histories. Occup. Environ. Med. 1997, 54, 194-201.
79. Nawrot, T.; Plusquin, M.; Hogervorst, J.; Roels, H. A.; Celis, H.; Thijs, L.; Vangronsveld, J.; Van Hecke, E.; Staessen, J. A. Environmental exposure to cadmium and risk of cancer: a prospective population-based study. Lancet Oncol. 2006, 7, 119-126.
80. Stayner, L.; Smith, R.; Thun, M.; Schnorr, T.; Lemen, R. A doseresponse analysis and quantitative assessment of lung cancer risk and occupational cadmium exposure. Ann. Epidemiol. 1992, 2, 177-194.
81. McCredie, M.; Stewart, J. H. Risk factors for kidney cancer in New South Wales. IV. Occupation. Br. J. Ind. Med. 1993, 50, 349-354.
82. Partanen, T.; Heikkila, P.; HERnberg, S.; Kauppinen, T.; Moneta, G.; Ojajarvi, A. Renal cell cancer and occupational exposure to chemical agents. Scand. J. Work Environ. Health 1991, 17, 231-239.
83. Sorahan, T.; Lister, A.; Gilthorpe, M. S.; Harrington, J. M. Mortality of copper cadmium alloy workers with special reference to lung cancer and non-malignant diseases of the respiratory system, 1946-92. Occup. Environ. Med. 1995, 52, 804-812.
84. Sorahan, T.; Esmen, N. A. Lung cancer mortality in UK nickelcadmium battery workers, 1947-2000. Occup. Environ. Med. 2004, 61, 108-116.
85. Stayner, L.; Smith, R.; Thun, M.; Schnorr, T.; Lemen, R. A quantitative assessment of lung cancer risk and occupational cadmium exposure. IARC Sci. Publ. 1992, 447-455.
86. De Palma, G.; Goldoni, M.; Catalani, S.; Carbognani, P.; Poli, D.; Mozzoni, P.; Acampa, O.; Internullo, E.; Rusca, M.; Apostoli, P. Metallic elements in pulmonary biopsies from lung cancer and control subjects. Acta Biomed. 2008, 79 (Suppl 1), 43-51.
87. Yaman, M.; Kaya, G.; Yekeler, H. Distribution of trace metal concentrations in paired cancerous and non-cancerous human stomach tissues. World J. Gastroenterol. 2007, 13, 612-618.
88. Gallagher, C. M.; Chen, J. J.; Kovach, J. S. Environmental cadmium and breast cancer risk. Aging (Albany. NY) 2010, 2, 804-814.
89. Akesson, A.; Julin, B.; Wolk, A. Long-term dietary cadmium intake and postmenopausal endometrial cancer incidence: a population-based prospective cohort study. Cancer Res. 2008, 68, 6435-6441.
90. Jackson, L. W.; Zullo, M. D.; Goldberg, J. M. The association between heavy metals, endometriosis and uterine myomas among premenopausal women: National Health and Nutrition Examination Survey 1999-2002. Hum. Reprod. 2008, 23, 679-687.
91. Kriegel, A. M.; Soliman, A. S.; Zhang, Q.; El Ghawalby, N.; Ezzat, F.; Soultan, A.; Abdel-Wahab, M.; Fathy, O.; Ebidi, G.; Bassiouni, N.; Hamilton, S. R.; Abbruzzese, J. L.; Lacey, M. R.; Blake, D. A. Serum cadmium levels in pancreatic cancer patients from the East Nile Delta region of Egypt. Environ. Health Perspect. 2006, 114, 113-119.
92. Gullick, W. J. Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. Br. Med. Bull. 1991, 47, 87-98.
93. Hirsch, F. R.; Varella-Garcia, M.; Bunn, P. A. Jr.; Di Maria, M. V.; Veve, R.; Bremmes, R. M.; Baron, A. E.; Zeng, C.; Franklin, W. A. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J. Clin. Oncol. 2003, 21, 3798-3807.
94. Salomon, D. S.; Brandt, R.; Ciardiello, F.; Normanno, N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit. Rev. Oncol. Hematol. 1995, 19, 183-232.
95. Suzuki, S.; Dobashi, Y.; Sakurai, H.; Nishikawa, K.; Hanawa, M.; Ooi, A. Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas. An immunohistochemical and fluorescence in situ hybridization study. Cancer 2005, 103, 1265-1273.
96. Normanno, N.; De Luca, A.; Bianco, C.; Strizzi, L.; Mancino, M.; Maiello, M. R.; Carotenuto, A.; De Feo, G., Caponigro, F.; Salomon, D. S. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006, 366, 2-16.
97. Mitsudomi, T.; Yatabe, Y. Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J. 2010, 277, 301-308.
98. Gullick, W. J. The epidermal growth factor system of ligands and receptors in cancer. Eur. J. Cancer 2009, 45 (Suppl 1), 205-210.
99. Andrew, A. S.; Mason, R. A.; Memoli, V.; Duell, E. J. Arsenic activates EGFR pathway signaling in the lung. Toxicol. Sci. 2009, 109, 350-357.
100. Chen, W.; Martindale, J. L.; Holbrook, N. J.; Liu, Y. Tumor promoter arsenite activates extracellular signal-regulated kinase through a signaling pathway mediated by epidermal growth factor receptor and Shc. Mol. Cell Biol. 1998, 18, 5178-5188.
101. Cooper, K. L.; Myers, T. A.; Rosenberg, M.; Chavez, M.; Hudson, L. G. Roles of mitogen activated protein kinases and EGF receptor in arsenite-stimulated matrix metalloproteinase-9 production. Toxicol. Appl. Pharmacol. 2004, 200, 177-185.
102. Ivanov, V. N.; Hei, T. K. Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFRpositive melanomas: a role of suppression of the PI3K-AKT pathway. Oncogene 2005, 24, 616-626.
103. Liu, L. Z.; Hu, X. W.; Xia, C.; He, J.; Zhou, Q.; Shi, X.; Fang, J.; Jiang, B. H. Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxiainducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radic. Biol. Med. 2006, 41, 1521-1533.
104. Nuntharatanapong, N.; Chen, K.; Sinhaseni, P.; Keaney, J. F. Jr. EGF receptor-dependent JNK activation is involved in arseniteinduced p21Cip1/Waf1 upregulation and endothelial apoptosis. Am. J. Physiol. Heart Circ. Physiol. 2005, 289, H99-H107.
105. Patterson, T. J.; Rice, R. H. Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. Toxicol. Appl. Pharmacol. 2007, 221, 119-128.
106. Simeonova, P. P.; Wang, S.; Hulderman, T.; Luster, M. I. c-Srcdependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by arsenic. Role in carcinogenesis. J. Biol. Chem. 2002, 277, 2945-2950.
107. Tanaka-Kagawa, T.; Hanioka, N.; Yoshida, H.; Jinno, H.; Ando, M. Arsenite and arsenate activate extracellular signal-regulated kinases 1/2 by an epidermal growth factor receptor-mediated pathway in normal human keratinocytes. Br. J. Dermatol. 2003, 149, 1116-1127.
108. Wen, G.; Hong, M.; Calaf, G. M.; Roy, D.; Partridge, M. A.; Li, B.; Hei, T. K. Phosphoproteomic profiling of arsenite-treated human small airway epithelial cells. Oncol. Rep. 2010, 23, 405-412.
109. Wu, W.; Jaspers, I.; Zhang, W.; Graves, L. M.; Samet, J. M. Role of Ras in metal-induced EGF receptor signaling and NF-kappaB activation in human airway epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2002, 282, L1040-L1048.
110. Mudipalli, A.; Owen, R. D.; Preston, R. J. The effect of arsenicals on ultraviolet-radiation-induced growth arrest and related signaling events in human keratinocytes. Int. J. Oncol. 2005, 27, 769-778.
111. Ouyang, W.; Li, J.; Zhang, D.; Jiang, B. H.; Huang, D. C. PI-3K/Akt signal pathway plays a crucial role in arsenite-induced cell proliferation of human keratinocytes through induction of cyclin D1. J. Cell Biochem. 2007, 101, 969-978.
112. Herbert, K. J.; Snow, E. T. Modulation of arsenic-induced epidermal growth factor receptor pathway signaling by resveratrol. Chem. Biol. Interact. 2012, 198, 38-48.
113. Wu, W.; Graves, L. M.; Jaspers, I.; Devlin, R. B.; Reed, W.; Samet, J. M. Activation of the EGF receptor signaling pathway in human airway epithelial cells exposed to metals. Am. J. Physiol. 1999, 277, L924-L931.
114. Ahmadibeni, Y.; Hanley, M.; White, M.; Ayrapetov, M.; Lin, X.; Sun, G.; Parang, K. Metal-binding properties of a dicysteinecontaining motif in protein tyrosine kinases. Chem. Bio. Chem. 2007, 8, 1592-1605.
115. Boots, A. W.; Hristova, M.; Kasahara, D. I.; Haenen, G. R.; Bast, A.; Vand, V. ATP-mediated activation of the NADPH oxidase DUOX1 mediates airway epithelial responses to bacterial stimuli. J. Biol. Chem. 2009, 284, 17858-17867.
116. Eblin, K. E.; Bredfeldt, T. G.; Buffington, S.; Gandolfi, A. J. Mitogenic signal transduction caused by monomethylarsonous acid in human bladder cells: role in arsenic-induced carcinogenesis. Toxicol. Sci. 2007, 95, 321-330.
117. Germolec, D. R.; Spalding, J.; Yu, H. S.; Chen, G. S.; Simeonova, P. P.; Humble, M. C.; Bruccoleri, A.; Boorman, G. A.; Foley, J. F.; Yoshida, T.; Luster, M. I. Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors. Am. J. Pathol. 1998, 153, 1775-1785.
118. Trouba, K. J.; Wauson, E. M.; Vorce, R. L. Sodium arseniteinduced dysregulation of proteins involved in proliferative signaling. Toxicol. Appl. Pharmacol. 2000, 164, 161-170.
119. Shen, J.; Liu, J.; Xie, Y.; Diwan, B. A.; Waalkes, M. P. Fetal onset of aberrant gene expression relevant to pulmonary carcinogenesis in lung adenocarcinoma development induced by in utero arsenic exposure. Toxicol. Sci. 2007, 95, 313-320.
120. Li, Y.; Chen, Y.; Slavkovic, V.; Ahsan, H.; Parvez, F.; Graziano, J. H.; Brandt-Rauf, P. W. Serum levels of the extracellular domain of the epidermal growth factor receptor in individuals exposed to arsenic in drinking water in Bangladesh. Biomarkers 2007, 12, 256-265.
121. Sung, T. I.; Wang, Y. J.; Chen, C. Y.; Hung, T. L.; Guo, H. R. Increased serum level of epidermal growth factor receptor in liver cancer patients and its association with exposure to arsenic. Sci. Total Environ. 2012, 424, 74-78.
122. Rodrigues, C. F.; Urbano, A. M.; Matoso, E.; Carreira, I.; Almeida, A.; Santos, P.; Botelho, F.; Carvalho, L.; Alves, M.; Monteiro, C.; Costa, A. N.; Moreno, V.; Alpoim, M. C. Human bronchial epithelial cells malignantly transformed by hexavalent chromium exhibit an aneuploid phenotype but no microsatellite instability. Mutat. Res. 2009, 670, 42-52.
123. Castorina, A.; Tiralongo, A.; Cavallo, D.; Loreto, C.; Carnazza, M. L.; Iavicoli, S.; D'Agata, V. Expression profile of ERBB receptor's family in human alveolar type 2-like cell line A549 exposed to hexavalent chromium. Toxicol. In Vitro 2008, 22, 541-547.
124. Wang, B. J.; Sheu, H. M.; Guo, Y. L.; Lee, Y. H.; Lai, C. S.; Pan, M. H.; Wang, Y. J. Hexavalent chromium induced ROS formation, Akt, NF-kappaB, and MAPK activation, and TNF-alpha and IL-1alpha production in keratinocytes. Toxicol. Lett. 2010, 198, 216-224.
125. O'Hara, K. A.; Vaghjiani, R. J.; Nemec, A. A.; Klei, L. R.; Barchowsky, A. Cr(VI)-stimulated STAT3 tyrosine phosphorylation and nuclear translocation in human airway epithelial cells requires Lck. Biochem. J. 2007, 402, 261-269.
126. Tveito, G.; Hansteen, I. L.; Dalen, H.; Haugen, A. Immortalization of normal human kidney epithelial cells by nickel(II). Cancer Res. 1989, 49, 1829-1835.
127. Mollerup, S.; Rivedal, E.; Moehle, L.; Haugen, A. Nickel(II) induces alterations in EGF-and TGF-beta 1-mediated growth control during malignant transformation of human kidney epithelial cells. Carcinogenesis 1996, 17, 361-367.
128. Giunta, S.; Castorina, A.; Scuderi, S.; Patti, C.; D'Agata, V. Epidermal growth factor receptor (EGFR) and neuregulin (Neu) activation in human airway epithelial cells exposed to nickel acetate. Toxicol. In Vitro 2012, 26, 74-78.
129. Chaudhry, I. S.; El Meanawy, A.; Khiyami, A.; Tomashefski, J. F.; Jr., Machekano, R. N.; Kass, L. Short-term exposure to tobacco toxins alters expression of multiple proliferation gene markers in primary human bronchial epithelial cell cultures. J. Oncol. 2011, 2011, 208563.
130. Lo, H. W.; Hsu, S. C.; Ali-Seyed, M.; Gunduz, M.; Xia, W.; Wei, Y.; Bartholomeusz, G.; Shih, J. Y.; Hung, M. C. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell 2005, 7, 575-589.
131. Li, Q.; Suen, T. C.; Sun, H.; Arita, A.; Costa, M. Nickel compounds induce apoptosis in human bronchial epithelial Beas-2B cells by activation of c-Myc through ERK pathway. Toxicol. Appl. Pharmacol. 2009, 235, 191-198.
132. Tessier, D. M.; Pascal, L. E. Activation of MAP kinases by hexavalent chromium, manganese and nickel in human lung epithelial cells. Toxicol. Lett. 2006, 167, 114-121.
133. Mongan, M.; Tan, Z.; Chen, L.; Peng, Z.; Dietsch, M.; Su, B.; Leikauf, G.; Xia, Y. Mitogen-activated protein kinase kinase kinase 1 protects against nickel-induced acute lung injury. Toxicol. Sci. 2008, 104, 405-411.
134. Pan, J.; Chang, Q.; Wang, X.; Son, Y.; Zhang, Z.; Chen, G.; Luo, J.; Bi, Y.; Chen, F.; Shi, X. Reactive oxygen species-activated Akt/ASK1/p38 signaling pathway in nickel compound-induced apoptosis in BEAS 2B cells. Chem. Res. Toxicol. 2010, 23, 568-577.
135. Ke, Q.; Li, Q.; Ellen, T. P.; Sun, H.; Costa, M. Nickel compounds induce phosphorylation of histone H3 at serine 10 by activating JNK-MAPK pathway. Carcinogenesis 2008, 29, 1276-1281.
136. Kundu, S.; Sengupta, S.; Bhattacharyya, A. EGFR upregulates inflammatory and proliferative responses in human lung adenocarcinoma cell line (A549), induced by lower dose of cadmium chloride. Inhal. Toxicol. 2011, 23, 339-348.
137. Misra, U. K.; Gawdi, G.; Pizzo, S. V. Induction of mitogenic signalling in the 1LN prostate cell line on exposure to submicromolar concentrations of cadmium+. Cell Signal. 2003, 15, 1059-1070.
138. Jing, Y.; Liu, L. Z.; Jiang, Y.; Zhu, Y.; Guo, N. L.; Barnett, J.; Rojanasakul, Y.; Agani, F.; Jiang, B. H. Cadmium increases HIF-1 and VEGF expression through ROS, ERK, and AKT signaling pathways and induces malignant transformation of human bronchial epithelial cells. Toxicol. Sci. 2012, 125, 10-19.
139. Thevenod, F. Cadmium and cellular signaling cascades: to be or not to be? Toxicol. Appl. Pharmacol. 2009, 238, 221-239.
140. Benbrahim-Tallaa, L.; Tokar, E. J.; Diwan, B. A.; Dill, A. L.; Coppin, J. F.; Waalkes, M. P. Cadmium malignantly transforms normal human breast epithelial cells into a basal-like phenotype. Environ. Health Perspect. 2009, 117, 1847-1852.
141. Brama, M.; Gnessi, L.; Basciani, S.; Cerulli, N.; Politi, L.; Spera, G.; Mariani, S.; Cherubini, S.; d'Abusco, A. S.; Scandurra, R.; Migliaccio, S. Cadmium induces mitogenic signaling in breast cancer cell by an ERalpha-dependent mechanism. Mol. Cell Endocrinol. 2007, 264, 102-108.
142. Jiang, B. H.; Liu, L. Z. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv. Cancer Res. 2009, 102, 19-65.
143. Jiang, B. H.; Liu, L. Z. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim. Biophys. Acta. 2008, 1784, 150-158.
144. Hresko, R. C.; Murata, H.; Mueckler, M. Phosphoinositidedependent kinase-2 is a distinct protein kinase enriched in a novel cytoskeletal fraction associated with adipocyte plasma membranes. J. Biol. Chem. 2003, 278, 21615-21622.
145. Sarbassov, D. D.; Guertin, D. A.; Ali, S. M.; Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005, 307, 1098-1101.
146. Stokoe, D.; Stephens, L. R.; Copeland, T.; Gaffney, P. R.; Reese, C. B.; Painter, G. F.; Holmes, A. B.; McCormick, F.; Hawkins, P. T. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science, 1997, 277, 567-570.
147. Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2, 489-501.
148. Hu, P.; Margolis, B.; Skolnik, E. Y.; Lammers, R.; Ullrich, A.; Schlessinger, J. Interaction of phosphatidylinositol 3-kinaseassociated p85 with epidermal growth factor and platelet-derived growth factor receptors. Mol. Cell Biol. 1992, 12, 981-990.
149. McGlade, C. J.; Ellis, C.; Reedijk, M.; Anderson, D.; Mbamalu, G.; Reith, A. D.; Panayotou, G.; End, P.; Bernstein, A.; Kazlauskas, A. SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors. Mol. Cell Biol. 1992, 12, 991-997.
150. Zhu, G.; Decker, S. J.; Saltiel, A. R. Direct analysis of the binding of Src-homology 2 domains of phospholipase C to the activated epidermal growth factor receptor. Proc. Natl. Acad. Sci. USA 1992, 89, 9559-9563.
151. Hennessy, B. T.; Smith, D. L.; Ram, P. T.; Lu, Y.; Mills, G. B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov. 2005, 4, 988-1004.
152. Carnero, A. The PKB/AKT pathway in cancer. Curr. Pharm. Des. 2010, 16, 34-44.
153. Gao, N.; Shen, L.; Zhang, Z.; Leonard, S. S.; He, H.; Zhang, X. G.; Shi, X.; Jiang, B. H. Arsenite induces HIF-1alpha and VEGF through PI3K, Akt and reactive oxygen species in DU145 human prostate carcinoma cells. Mol. Cell Biochem. 2004, 255, 33-45.
154. Lee, K. M.; Hwang, M. K.; Lee, D. E.; Lee, K. W.; Lee, H. J. Protective effect of quercetin against arsenite-induced COX-2 expression by targeting PI3K in rat liver epithelial cells. J. Agric. Food Chem. 2010, 58, 5815-5820.
155. Ouyang, W.; Li, J.; Ma, Q.; Huang, C. Essential roles of PI-3K/Akt/IKKbeta/NFkappaB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells. Carcinogenesis 2006, 27, 864-873.
156. Ouyang, W.; Luo, W.; Zhang, D.; Jian, J.; Ma, Q.; Li, J.; Shi, X.; Chen, J.; Gao, J.; Huang, C. PI-3K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation. Environ. Health Perspect. 2008, 116, 1-6.
157. Wang, Z.; Yang, J.; Fisher, T.; Xiao, H.; Jiang, Y.; Yang, C. Akt activation is responsible for enhanced migratory and invasive behavior of arsenic-transformed human bronchial epithelial cells. Environ. Health Perspect. 2012, 120, 92-97.
158. Liu, Y.; Hock, J. M.; Sullivan, C.; Fang, G.; Cox, A. J.; Davis, K. T.; Davis, B. H.; Li, X. Activation of the p38 MAPK/Akt/ERK1/2 signal pathways is required for the protein stabilization of CDC6 and cyclin D1 in low-dose arsenite-induced cell proliferation. J. Cell Biochem. 2010, 111, 1546-1555.
159. Kim, S.; Lee, S. H.; Kang, S.; Lee, L.; Park, J. D.; Ryu, D. Y. Involvement of c-Met-and phosphatidylinositol 3-kinase dependent pathways in arsenite-induced downregulation of catalase in hepatoma cells. Biol. Pharm. Bull. 2011, 34, 1748-1752.
160. Hossain, K.; Akhand, A. A.; Kawamoto, Y.; Du, J.; Takeda, K.; Wu, J.; Yoshihara, M.; Tsuboi, H.; Kato, M.; Suzuki, H.; Nakashima, I. Caspase activation is accelerated by the inhibition of arsenite-induced, membrane rafts-dependent Akt activation. Free Radic. Biol. Med. 2003, 34, 598-606.
161. Sandoval, M.; Morales, M.; Tapia, R.; del Carmen, A. L.; Sordo, M.; Ostrosky-Wegman, P.; Ortega, A.; Lopez-Bayghen, E. p53 response to arsenic exposure in epithelial cells: protein kinase B/Akt involvement. Toxicol. Sci. 2007, 99, 126-140.
162. Souza, K.; Maddock, D. A.; Zhang, Q.; Chen, J.; Chiu, C.; Mehta, S.; Wan, Y. Arsenite activation of P13K/AKT cell survival pathway is mediated by p38 in cultured human keratinocytes. Mol. Med. 2001, 7, 767-772.
163. Carpenter, R. L.; Jiang, Y.; Jing, Y.; He, J.; Rojanasakul, Y.; Liu, L. Z.; Jiang, B. H. Arsenite induces cell transformation by reactive oxygen species, AKT, ERK1/2, and p70S6K1. Biochem. Biophys. Res. Commun. 2011, 414, 533-538.
164. Skinner, H. D.; Zhong, X. S.; Gao, N.; Shi, X.; Jiang, B. H. Arsenite induces p70S6K1 activation and HIF-1alpha expression in prostate cancer cells. Mol. Cell Biochem. 2004, 255, 19-23.
165. Ding, J.; Ning, B.; Huang, Y.; Zhang, D.; Li, J.; Chen, C. Y.; Huang, C. PI3K/Akt/JNK/c-Jun signaling pathway is a mediator for arsenite-induced cyclin D1 expression and cell growth in human bronchial epithelial cells. Curr. Cancer Drug Targets 2009, 9, 500-509.
166. Patterson, T. J.; Reznikova, T. V.; Phillips, M. A.; Rice, R. H. Arsenite maintains germinative state in cultured human epidermal cells. Toxicol. Appl. Pharmacol. 2005, 207, 69-77.
167. Watcharasit, P.; Suntararuks, S.; Visitnonthachai, D.; Thiantanawat, A.; Satayavivad, J. β-catenin involvement in arsenite-induced VEGF expression in neuroblastoma SH-SY5Y cells. Environ. Toxicol. 2012, 26, 280-287.
168. Ghosh, N.; Chaki, R.; Mandal, V.; Mandal, S. C. COX-2 as a target for cancer chemotherapy. Pharmacol. Rep. 2010, 62, 233-244.
169. Jung, D. K.; Bae, G. U.; Kim, Y. K.; Han, S. H.; Choi, W. S.; Kang, H.; Seo, D. W.; Lee, H. Y.; Cho, E. J.; Lee, H. W.; Han, J. W. Hydrogen peroxide mediates arsenite activation of p70(s6k) and extracellular signal-regulated kinase. Exp. Cell Res. 2003, 290, 144-154.
170. He, Z.; Ma, W. Y.; Liu, G.; Zhang, Y.; Bode, A. M.; Dong, Z. Arsenite-induced phosphorylation of histone H3 at serine 10 is mediated by Akt1, extracellular signal-regulated kinase 2, and p90 ribosomal S6 kinase 2 but not mitogen-and stress-activated protein kinase 1. J. Biol. Chem. 2003, 278, 10588-10593.
171. Chen, B.; Liu, J.; Chang, Q.; Beezhold, K.; Lu, Y.; Chen, F. JNK and STAT3 signaling pathways converge on Akt-mediated phosphorylation of EZH2 in bronchial epithelial cells induced by arsenic. Cell Cycle 2012, 12, 112-121.
172. Kao, Y. H.; Yu, C. L.; Chang, L. W.; Yu, H. S. Low concentrations of arsenic induce vascular endothelial growth factor and nitric oxide release and stimulate angiogenesis in vitro. Chem. Res. Toxicol. 2003, 16, 460-468.
173. Watcharasit, P.; Visitnonthachai, D.; Suntararuks, S.; Thiantanawat, A.; Satayavivad, J. Low arsenite concentrations induce cell proliferation via activation of VEGF signaling in human neuroblastoma SH-SY5Y cells. Environ. Toxicol. Pharmacol. 2012, 33, 53-59.
174. Liu, L. Z.; Jiang, Y.; Carpenter, R. L.; Jing, Y.; Peiper, S. C.; Jiang, B. H. Role and mechanism of arsenic in regulating angiogenesis. PLoS. One 2011, 6, e20858.
175. Soucy, N. V.; Ihnat, M. A.; Kamat, C. D.; Hess, L.; Post, M. J.; Klei, L. R.; Clark, C.; Barchowsky, A. Arsenic stimulates angiogenesis and tumorigenesis in vivo. Toxicol. Sci. 2003, 76, 271-279.
176. Liu, J.; Chen, B.; Lu, Y.; Guan, Y.; Chen, F. JNK-dependent Stat3 phosphorylation contributes to Akt activation in response to arsenic exposure. Toxicol. Sci. 2012, 129, 363-371.
177. Beaver, L. M.; Stemmy, E. J.; Constant, S. L.; Schwartz, A.; Little, L. G.; Gigley, J. P.; Chun, G.; Sugden, K. D.; Ceryak, S. M.; Patierno, S. R. Lung injury, inflammation and Akt signaling following inhalation of particulate hexavalent chromium. Toxicol. Appl. Pharmacol. 2009, 235, 47-56.
178. Lal, M. A.; Bae, D.; Camilli, T. C.; Patierno, S. R.; Ceryak, S. AKT1 mediates bypass of the G1/S checkpoint after genotoxic stress in normal human cells. Cell Cycle 2009, 8, 1589-1602.
179. Li, J.; Davidson, G.; Huang, Y.; Jiang, B. H.; Shi, X.; Costa, M.; Huang, C. Nickel compounds act through phosphatidylinositol-3-kinase/Akt-dependent, p70(S6k)-independent pathway to induce hypoxia inducible factor transactivation and Cap43 expression in mouse epidermal Cl41 cells. Cancer Res. 2004, 64, 94-101.
180. Eckers, A.; Reimann, K.; Klotz, L. O. Nickel and copper ioninduced stress signaling in human hepatoma cells: analysis of phosphoinositide 3'-kinase/Akt signaling. Biometals 2009, 22, 307-316.
181. Gao, F.; Brant, K. A.; Ward, R. M.; Cattley, R. T.; Barchowsky, A.; Fabisiak, J. P. Multiple protein kinase pathways mediate amplified IL-6 release by human lung fibroblasts co-exposed to nickel and TLR-2 agonist, MALP-2. Toxicol. Appl. Pharmacol. 2010, 247, 146-157.
182. Pan, J.J.; Chang, Q.S.; Wang, X.; Son, Y.O.; Liu, J.; Zhang, Z.; Bi, Y.Y.; Shi, X. Activation of Akt/GSK3β and Akt/Bcl-2 signaling pathways in nickel-transformed BEAS-2B cells. Int. J. Oncol. 2011, 39, 1285-1294.
183. Ara, T.; Declerck, Y. A. Interleukin-6 in bone metastasis and cancer progression. Eur. J. Cancer 2010, 46, 1223-1231.
184. Kim, S. M.; Park, J. G.; Baek, W. K.; Suh, M. H.; Lee, H.; Yoo, S. K.; Jung, K. H.; Suh, S. I.; Jang, B. C. Cadmium specifically induces MKP-1 expression via the glutathione depletion-mediated p38 MAPK activation in C6 glioma cells. Neurosci. Lett. 2008, 440, 289-293.
185. Lee, Y. J.; Lee, G. J.; Baek, B. J.; Heo, S. H.; Won, S. Y.; Im, J. H.; Cho, M. K.; Nam, H. S.; Lee, S. H. Cadmium-induced upregulation of aldo-keto reductase 1C3 expression in human nasal septum carcinoma RPMI-2650 cells: Involvement of reactive oxygen species and phosphatidylinositol 3-kinase/Akt. Environ. Toxicol. Pharmacol. 2011, 31, 469-478.
186. Chen, L.; Xu, B.; Liu, L.; Luo, Y.; Zhou, H.; Chen, W.; Shen, T.; Han, X.; Kontos, C. D.; Huang, S. Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death. Free Radic. Biol. Med. 2011, 50, 624-632.
187. Xu, B.; Chen, S.; Luo, Y.; Chen, Z.; Liu, L.; Zhou, H.; Chen, W.; Shen, T.; Han, X.; Chen, L.; Huang, S. Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR network. PLoS. One 2011, 6, e19052.
188. Kundu, S.; Sengupta, S.; Chatterjee, S.; Mitra, S.; Bhattacharyya, A. Cadmium induces lung inflammation independent of lung cell proliferation: a molecular approach. J. Inflamm.(Lond) 2009, 6, 19.
189. Liu, Z.; Yu, X.; Shaikh, Z. A. Rapid activation of ERK1/2 and AKT in human breast cancer cells by cadmium. Toxicol. Appl. Pharmacol. 2008, 228, 286-294.
190. Liu, Z. M.; Chen, G. G.; Vlantis, A. C.; Tse, G. M.; Shum, C. K.; van Hasselt, C. A. Calcium-mediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells. Cell Mol. Life Sci. 2007, 64, 1428-1436.
191. Xiao, W.; Liu, Y.; Templeton, D. M. Pleiotropic effects of cadmium in mesangial cells. Toxicol. Appl. Pharmacol. 2009, 238, 315-326.
192. Son, Y. O.; Wang, L.; Poyil, P.; Budhraja, A.; Hitron, J. A.; Zhang, Z.; Lee, J. C.; Shi, X. Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of PI3K/AKT/GSK-3β/β-catenin signaling. Toxicol. Appl. Pharmacol. 2012, 264, 153-160.
193. Simoncini, T.; Hafezi-Moghadam, A.; Brazil, D. P.; Ley, K.; Chin, W. W.; Liao, J. K. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000, 407, 538-541.
194. Foster, K. G.; Fingar, D. C. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J. Biol. Chem. 2010, 285, 14071-14077.
195. Dunlop, E. A.; Dodd, K. M.; Seymour, L. A.; Tee, A. R. Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition. Cell Signal. 2009, 21, 1073-1084.
196. Nojima, H.; Tokunaga, C.; Eguchi, S.; Oshiro, N.; Hidayat, S.; Yoshino, K.; Hara, K.; Tanaka, N.; Avruch, J.; Yonezawa, K. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J. Biol. Chem. 2003, 278, 15461-15464.
197. Schalm, S. S.; Fingar, D. C.; Sabatini, D. M.; Blenis, J. TOS motifmediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 2003, 13, 797-806.
198. Sato, T.; Nakashima, A.; Guo, L.; Tamanoi, F. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J. Biol. Chem. 2009, 284, 12783-12791.
199. Inoki, K.; Zhu, T.; Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003, 115, 577-590.
200. Tremblay, F.; Marette, A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J. Biol. Chem. 2001, 276, 38052-38060.
201. Wu, X. N.; Wang, X. K.; Wu, S. Q.; Lu, J.; Zheng, M.; Wang, Y. H.; Zhou, H.; Zhang, H.; Han, J. Phosphorylation of Raptor by p38beta participates in arsenite-induced mammalian target of rapamycin complex 1 (mTORC1) activation. J. Biol. Chem. 2011, 286, 31501-31511.
202. Wang, X.; Proud, C. G. p70 S6 kinase is activated by sodium arsenite in adult rat cardiomyocytes: roles for phosphatidylinositol 3-kinase and p38 MAP kinase. Biochem. Biophys. Res. Commun. 1997, 238, 207-212.
203. Patel, J.; McLeod, L. E.; Vries, R. G.; Flynn, A.; Wang, X.; Proud, C. G. Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors. Eur. J Biochem. 2002, 269, 3076-3085.
204. Bae, G. U.; Kim, Y. K.; Kwon, H. K.; Park, J. W.; Lee, E. K.; Paek, S. J.; Choi, W. S.; Jung, I. D.; Lee, H. Y.; Cho, E. J.; Lee, H. W.; Han, J. W. Hydrogen peroxide mediates Rac1 activation of S6K1. Exp. Cell Res. 2004, 300, 476-484.
205. Inoki, K.; Li, Y.; Zhu, T.; Wu, J.; Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 2002, 4, 648-657.
206. Potter, C. J.; Pedraza, L. G.; Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 2002, 4, 658-665.
207. Sancak, Y.; Thoreen, C. C.; Peterson, T. R.; Lindquist, R. A.; Kang, S. A.; Spooner, E.; Carr, S. A.; Sabatini, D. M. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 2007, 25, 903-915.
208. Vander, H. E.; Lee, S. I.; Bandhakavi, S.; Griffin, T. J.; Kim, D. H. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 2007, 9, 316-323.
209. Wang, L.; Harris, T. E.; Roth, R. A.; Lawrence, J. C. Jr. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J. Biol. Chem. 2007, 282, 20036-20044.
210. Ouyang, W.; Li, J.; Shi, X.; Costa, M.; Huang, C. Essential role of PI-3K, ERKs and calcium signal pathways in nickel-induced VEGF expression. Mol. Cell Biochem. 2005, 279, 35-43.
211. Davidson, T. L.; Chen, H.; Di Toro, D. M.; D'Angelo, G.; Costa, M. Soluble nickel inhibits HIF-prolyl-hydroxylases creating persistent hypoxic signaling in A549 cells. Mol. Carcinog. 2006, 45, 479-489.
212. Chen, L.; Liu, L.; Luo, Y.; Huang, S. MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J. Neurochem. 2008, 105, 251-261.
213. Chen, S.; Xu, Y.; Xu, B.; Guo, M.; Zhang, Z.; Liu, L.; Ma, H.; Chen, Z.; Luo, Y.; Huang, S.; Chen, L. CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death. J. Neurochem. 2011, 119, 1108-1118.
214. Fang, J.; Zhou, Q.; Liu, L. Z.; Xia, C.; Hu, X.; Shi, X.; Jiang, B. H. Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression. Carcinogenesis 2007, 28, 858-864.
215. Fang, J.; Xia, C.; Cao, Z.; Zheng, J. Z.; Reed, E. Jiang, B. H. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/ p70S6K1 and HDM2/p53 pathways. FASEB J. 2005, 19, 342-353.
216. Liu, L. Z.; Fang, J.; Zhou, Q.; Hu, X.; Shi, X.; Jiang, B. H. Apigenin inhibits expression of vascular endothelial growth factor and angiogenesis in human lung cancer cells: implication of chemoprevention of lung cancer. Mol. Pharmacol. 2005, 68, 635-643.
217. Luo, H.; Jiang, B. H.; King, S. M.; Chen, Y. C. Inhibition of cell growth and VEGF expression in ovarian cancer cells by flavonoids. Nutr. Cancer 2008, 60, 800-809.
218. Masuelli, L.; Marzocchella, L.; Quaranta, A.; Palumbo, C.; Pompa, G.; Izzi, V.; Canini, A.; Modesti, A.; Galvano, F.; Bei, R. Apigenin induces apoptosis and impairs head and neck carcinomas EGFR/ERBB2 signaling. Front. Biosci. 2011, 16, 1060-1068.
219. Cao, Z.; Fang, J.; Xia, C.; Shi, X.; Jiang, B. H. trans-3,4,5'-Trihydroxystibene inhibits hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression in human ovarian cancer cells. Clin. Cancer Res. 2004, 10, 5253-5263.
220. He, X.; Wang, Y.; Zhu, J.; Orloff, M.; Eng, C. Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signaling. Cancer Lett. 2011, 301, 168-176.
221. Jiang, H.; Shang, X.; Wu, H.; Gautam, S. C.; Al Holou, S.; Li, C.; Kuo, J.; Zhang, L.; Chopp, M. Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J. Exp. Ther. Oncol. 2009, 8, 25-33.
222. Stewart, J. R.; O'Brian, C. A. Resveratrol antagonizes EGFRdependent Erk1/2 activation in human androgen-independent prostate cancer cells with associated isozyme-selective PKC alpha inhibition. Invest. New Drugs 2004, 22, 107-117.
223. Athar, M.; Back, J. H.; Kopelovich, L.; Bickers, D. R.; Kim, A. L. Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms. Arch. Biochem. Biophys. 2009, 486, 95-102.
224. Gupta, S. C.; Kim, J. H.; Prasad, S.; Aggarwal, B. B. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev. 2010, 29, 405-434.
225. Leonard, S. S.; Xia, C.; Jiang, B. H.; Stinefelt, B.; Klandorf, H.; Harris, G. K.; Shi, X. Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem. Biophys. Res. Commun. 2003, 309, 1017-1026.
226. Shehzad, A.; Wahid, F.; Lee, Y. S. Curcumin in cancer chemoprevention: molecular targets, pharmacokinetics, bioavailability, and clinical trials. Arch. Pharm.(Weinheim) 2010, 343, 489-499.
227. Campbell, L.; Blackhall, F.; Thatcher, N. Gefitinib for the treatment of non-small-cell lung cancer. Expert. Opin. Pharmacother. 2010, 11, 1343-1357.
228. Garlich, J. R.; De, P.; Dey, N.; Su, J. D.; Peng, X.; Miller, A.; Murali, R.; Lu, Y.; Mills, G. B.; Kundra, V.; Shu, H. K.; Peng, Q.; Durden, D. L. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res. 2008, 68, 206-215.
229. Dudkin, L.; Dilling, M. B.; Cheshire, P. J.; Harwood, F. C.; Hollingshead, M.; Arbuck, S. G.; Travis, R.; Sausville, E. A.; Houghton, P. J. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin. Cancer Res. 2001, 7, 1758-1764.
230. Hudes, G.; Carducci, M.; Tomczak, P.; Dutcher, J.; Figlin, R.; Kapoor, A.; Staroslawska, E.; Sosman, J.; McDermott, D.; Bodrogi, I.; Kovacevic, Z.; Lesovoy, V.; Schmidt-Wolf, I. G.; Barbarash, O.; Gokmen, E.; O'Toole, T.; Lustgarten, S.; Moore, L.; Motzer, R. J. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 2007, 356, 2271-2281.
231. Sun, S. Y.; Rosenberg, L. M.; Wang, X.; Zhou, Z.; Yue, P.; Fu, H.; Khuri, F. R. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005, 65, 7052-7058.
232. Maira, S. M.; Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.; Brachmann, S.; Chene, P.; De Pover, A.; Schoemaker, K.; Fabbro, D.; Gabriel, D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers, W.; Garcia-Echeverria, C. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther. 2008, 7, 1851-1863.
233. Baumann, P.; Mandl-Weber, S.; Oduncu, F.; Schmidmaier, R. The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp. Cell Res. 2009, 315, 485-497.
234. Cao, P.; Maira, S. M.; Garcia-Echeverria, C.; Hedley, D. W. Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. Br. J. Cancer 2009, 100, 1267-1276.
235. Marone, R.; Erhart, D.; Mertz, A. C.; Bohnacker, T.; Schnell, C.; Cmiljanovic, V.; Stauffer, F.; Garcia-Echeverria, C.; Giese, B.; Maira, S. M.; Wymann, M. P. Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors. Mol. Cancer Res. 2009, 7, 601-613.
236. McMillin, D. W.; Ooi, M.; Delmore, J.; Negri, J.; Hayden, P.; Mitsiades, N.; Jakubikova, J.; Maira, S. M.; Garcia-Echeverria, C.; Schlossman, R.; Munshi, N. C.; Richardson, P. G.; Anderson, K. C.; Mitsiades, C. S. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res. 2009, 69, 5835-5842.