The effects of berry extracts on cell signaling pathways: Leading to cellular transformation

Berries and Cancer Prevention

Volumn , Issue , 2011, Pages 51-75

  Cai, Tongjian ^a   Huang, Chuanshu ^a  

^a NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Berry extracts; Cellular transformation; Signaling pathways

Indexed keywords

EID: 84862176307     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-1-4419-7554-6_3     Document Type: Chapter

References (152)

1. Acevedo VD, Ittmann M, Spencer DM (2009) Paths of FGFR-driven tumorigenesis. Cell Cycle 8:580-588
2. Afaq F, Zaman N, Khan N, Syed DN, Sarfaraz S, Zaid MA, Mukhtar H (2008) Inhibition of epidermal growth factor receptor signaling pathway by delphinidin, an anthocyanidin in pigmented fruits and vegetables. Int J Cancer 123:1508-1515
3. Agarwal S, Achari C, Praveen D, Roy KR, Reddy GV, Reddanna P (2009) Inhibition of 12-LOX and COX-2 reduces the proliferation of human epidermoid carcinoma cells (A431) by modulating the ERK and PI3K-Akt signalling pathways. Exp Dermatol 18:939-946
4. Aggarwal BB, Gehlot P (2009) Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 9:351-369
5. Ahmed KM, Li JJ (2008) NF-kappa B-mediated adaptive resistance to ionizing radiation. Free Radic Biol Med 44:1-13
6. Ahn EH, Schroeder JJ (2006) Sphinganine causes early activation of JNK and p38 MAPK and inhibition of AKT activation in HT-29 human colon cancer cells. Anticancer Res 26:121-127
7. Assinder SJ, Dong Q, Kovacevic Z, Richardson DR (2009) The TGF-beta, PI3K/Akt and PTEN pathways: established and proposed biochemical integration in prostate cancer. Biochem J 417:411-421
8. Atsumi T, Kato K, Uno K, Iijima K, Koike T, Imatani A, Ohara S, Shimosegawa T (2007) Pathophysiological role of the activation of p38 mitogen-activated protein kinases in poorly differentiated gastric cancer. Pathol Int 57:635-644
9. Baek SJ, Eling TE (2006) Changes in gene expression contribute to cancer prevention by COX inhibitors. Prog Lipid Res 45:1-16
10. Bagchi D, Sen CK, Bagchi M, Atalay M (2004) Anti-angiogenic, antioxidant, and anti-carcinogenic properties of a novel anthocyanin-rich berry extract formula. Biochemistry 69:75-80, 71 p preceding 75
11. Bai D, Ueno L, Vogt PK (2009) Akt-mediated regulation of NFkappaB and the essentialness of NFkappaB for the oncogenicity of PI3K and Akt. Int J Cancer 125:2863-2870
12. Bellezza I, Bracarda S, Caserta C, Minelli A (2006) Targeting of EGFR tyrosine kinase by ZD1839 ("Iressa") in androgen-responsive prostate cancer in vitro. Mol Genet Metab 88:114-122
13. Bocca C, Bozzo F, Cannito S, Colombatto S, Miglietta A (2010) CLA reduces breast cancer cell growth and invasion through ERalpha and PI3K/Akt pathways. Chem Biol Interact 183:187-193
14. Bogoyevitch MA, Kobe B (2006) Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases. Microbiol Mol Biol Rev 70:1061-1095
15. Boivin D, Blanchette M, Barrette S, Moghrabi A, Beliveau R (2007) Inhibition of cancer cell proliferation and suppression of TNF-induced activation of NFkappaB by edible berry juice. Anticancer Res 27:937-948
16. Bremnes RM, Camps C, Sirera R (2006) Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. Lung Cancer 51:143-158
17. Cakir M, Grossman AB (2009) Targeting MAPK (Ras/ERK) and PI3K/Akt pathways in pituitary tumorigenesis. Expert Opin Ther Targets 13:1121-1134
18. Cao XH, Wang AH, Wang CL, Mao DZ, Lu MF, Cui YQ, Jiao RZ (2010) Surfactin induces apop-tosis in human breast cancer MCF-7 cells through a ROS/JNK-mediated mitochondrial/caspase pathway. Chem Biol Interact 183:357-362
19. Cardones AR, Banez LL (2006) VEGF inhibitors in cancer therapy. Curr Pharm Des 12:387-394
20. Carmeliet P (2005) VEGF as a key mediator of angiogenesis in cancer. Oncology 69(Suppl 3):4-10
21. Castellone MD, Carlomagno F, Salvatore G, Santoro M (2008) Receptor tyrosine kinase inhibitors in thyroid cancer. Best Pract Res 22:1023-1038
22. Cha YI, DuBois RN (2007) NSAIDs and cancer prevention: targets downstream of COX-2. Annu Rev Med 58:239-252
23. Chen FL, Armstrong AJ, George DJ (2008) Cell signaling modifiers in prostate cancer. Cancer J 14:40-45
24. Chen L, Mayer JA, Krisko TI, Speers CW, Wang T, Hilsenbeck SG, Brown PH (2009) Inhibition of the p38 kinase suppresses the proliferation of human ER-negative breast cancer cells. Cancer Res 69:8853-8861
25. Chen T, Rose ME, Hwang H, Nines RG, Stoner GD (2006) Black raspberries inhibit N-nitrosomethylbenzylamine (NMBA)-induced angiogenesis in rat esophagus parallel to the suppression of COX-2 and iNOS. Carcinogenesis 27:2301-2307
26. Chien CS, Shen KH, Huang JS, Ko SC, Shih YW (2010) Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem 333:169-180
27. Chow JY, Ban M, Wu HL, Nguyen F, Huang M, Chung H, Dong H, Carethers JM (2010) TGF-beta downregulates PTEN via activation of NF-kappaB in pancreatic cancer cells. Am J Physiol 298:G275-G282
28. Cooke D, Steward WP, Gescher AJ, Marczylo T (2005) Anthocyans from fruits and vegetables-does bright colour signal cancer chemopreventive activity? Eur J Cancer 41:1931-1940
29. Cooper JB, Cohen EE (2009) Mechanisms of resistance to EGFR inhibitors in head and neck cancer. Head & Neck 31:1086-1094
30. Dai J, Peng L, Fan K, Wang H, Wei R, Ji G, Cai J, Lu B, Li B, Zhang D, Kang Y, Tan M, Qian W, Guo Y (2009) Osteopontin induces angiogenesis through activation of PI3K/AKT and ERK1/2 in endothelial cells. Oncogene 28:3412-3422
31. Daouti S, Wang H, Li WH, Higgins B, Kolinsky K, Packman K, Specian A Jr, Kong N, Huby N, Wen Y, Xiang Q, Podlaski FJ, He Y, Fotouhi N, Heimbrook D, Niu H (2009) Characterization of a novel mitogen-activated protein kinase kinase 1/2 inhibitor with a unique mechanism of action for cancer therapy. Cancer Res 69:1924-1932
32. Dhanasekaran DN, Reddy EP (2008) JNK signaling in apoptosis. Oncogene 27:6245-6251
33. Dhand R, Hiles I, Panayotou G, Roche S, Fry MJ, Gout I, Totty NF, Truong O, Vicendo P, Yonezawa K et al. (1994) PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J 13:522-533
34. Ding M, Feng R, Wang SY, Bowman L, Lu Y, Qian Y, Castranova V, Jiang BH, Shi X (2006b) Cyanidin-3-glucoside, a natural product derived from blackberry, exhibits chemopreventive and chemotherapeutic activity. J Biol Chem 281:17359-17368
35. Ding J, Huang Y, Ning B, Gong W, Li J, Wang H, Chen CY, Huang C (2009a) TNF-alpha induction by nickel compounds is specific through ERKs/AP-1-dependent pathway in human bronchial epithelial cells. Curr Cancer Drug Targets 9:81-90
36. Ding J, Li J, Chen J, Chen H, Ouyang W, Zhang R, Xue C, Zhang D, Amin S, Desai D, Huang C (2006a) Effects of polycyclic aromatic hydrocarbons (PAHs) on vascular endothelial growth factor induction through phosphatidylinositol 3-kinase/AP-1-dependent, HIF-1alpha-independent pathway. J Biol Chem 281:9093-9100
37. Ding J, Ning B, Huang Y, Zhang D, Li J, Chen CY, Huang C (2009b) 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 9:500-509
38. Du F, Wang L, Qian W, Liu S (2009) Loss of enteric neurons accompanied by decreased expression of GDNF and PI3K/Akt pathway in diabetic rats. Neurogastroenterol Motil 21: 1229-e1114
39. D'Acquisto F, May MJ, Ghosh S (2002) Inhibition of nuclear factor kappa B (NF-B): an emerging theme in anti-inflammatory therapies. Mol Interv 2:22-35
40. Feng R, Bowman LL, Lu Y, Leonard SS, Shi X, Jiang BH, Castranova V, Vallyathan V, Ding M (2004) Blackberry extracts inhibit activating protein 1 activation and cell transformation by perturbing the mitogenic signaling pathway. Nutr Cancer 50:80-89
41. Ferrara N (2005) VEGF as a therapeutic target in cancer. Oncology 69(Suppl 3):11-16
42. Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161:851-858
43. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391-400
44. Ferrara N, Hillan KJ, Novotny W (2005) Bevacizumab (avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333:328-335
45. Ferrara N, Mass RD, Campa C, Kim R (2007) Targeting VEGF-A to treat cancer and age-related macular degeneration. Annu Rev Med 58:491-504
46. Fister S, Gunthert AR, Aicher B, Paulini KW, Emons G, Grundker C (2009) GnRH-I antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells via activation of stress-induced MAPKs p38 and JNK and proapoptotic protein bax. Cancer Res 69:6473-6481
47. Fu H, Hu Z, Wen J, Wang K, Liu Y (2009) TGF-beta promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways. Acta Biochim Biophys Sin 41:648-656
48. Gao JL, Shi JM, He K, Zhang QW, Li SP, Lee SM, Wang YT (2008) Yanhusuo extract inhibits metastasis of breast cancer cells by modulating mitogen-activated protein kinase signaling pathways. Oncol Rep 20:819-824
49. Garcia-Echeverria C, Sellers WR (2008) Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27:5511-5526
50. Goldmann WH, Sharma AL, Currier SJ, Johnston PD, Rana A, Sharma CP (2001) Saw palmetto berry extract inhibits cell growth and Cox-2 expression in prostatic cancer cells. Cell Biol Int 25:1117-1124
51. Gopalakrishnan A, Tony Kong AN (2008) Anticarcinogenesis by dietary phytochemicals: cytopro-tection by nrf2 in normal cells and cytotoxicity by modulation of transcription factors NF-kappa B and AP-1 in abnormal cancer cells. Food Chem Toxicol 46:1257-1270
52. Gouni-Berthold I, Sachinidis A (2004) Molecular mechanisms explaining the preventive effects of catechins on the development of proliferative diseases. CurrPharm Des 10:1261-1271
53. Gross ME, Jo S, Agus DB (2004) Update on HER-kinase-directed therapy in prostate cancer. Clin Adv Hematol Oncol 2:53-56
54. Gu M, Roy S, Raina K, Agarwal C, Agarwal R (2009) Inositol hexaphosphate suppresses growth and induces apoptosis in prostate carcinoma cells in culture and nude mouse xenograft: PI3K-Akt pathway as potential target. Cancer Res 69:9465-9472
55. Guo X, Ma N, Wang J, Song J, Bu X, Cheng Y, Sun K, Xiong H, Jiang G, Zhang B, Wu M, Wei L (2008) Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells. BMC Cancer 8:375
56. Han YC, Zeng XX, Wang R, Zhao Y, Li BL, Song M (2007) Correlation of p38 mitogen-activated protein kinase signal transduction pathway to uPA expression in breast cancer. Chin J Cancer 26:48-53
57. Harris GK, Gupta A, Nines RG, Kresty LA, Habib SG, Frankel WL, LaPerle K, Gallaher DD, Schwartz SJ, Stoner GD (2001) Effects of lyophilized black raspberries on azoxymethane-induced colon cancer and 8-hydroxy-2'-deoxyguanosine levels in the Fischer 344 rat. Nutr Cancer 40:125-133
58. He D, Xu Q, Yan M, Zhang P, Zhou X, Zhang Z, Duan W, Zhong L, Ye D, Chen W (2009) The NF-kappa B inhibitor, celastrol, could enhance the anti-cancer effect of gambogic acid on oral squamous cell carcinoma. BMC Cancer 9:343
59. Hecht SS, Huang C, Stoner GD, Li J, Kenney PM, Sturla SJ, Carmella SG (2006) Identification of cyanidin glycosides as constituents of freeze-dried black raspberries which inhibit anti-benzo[a]pyrene-7, 8-diol-9, 10-epoxide induced NFkappaB and AP-1 activity. Carcinogenesis 27:1617-1626
60. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18:813-822
61. Huang C, Huang Y, Li J, Hu W, Aziz R, Tang MS, Sun N, Cassady J, Stoner GD (2002) Inhibition of benzo(a)pyrene diol-epoxide-induced transactivation of activated protein 1 and nuclear factor kappaB by black raspberry extracts. Cancer Res 62:6857-6863
62. Huang C, Li J, Ding M, Leonard SS, Wang L, Castranova V, Vallyathan V, Shi X (2001) UV induces phosphorylation of protein kinase B (Akt) at Ser-473 and Thr-308 in mouse epidermal Cl 41 cells through hydrogen peroxide. J Biol Chem 276:40234-40240
63. Huang C, Li J, Ma WY, Dong Z (1999a) JNK activation is required for JB6 cell transformation induced by tumor necrosis factor-alpha but not by 12-O-tetradecanoylphorbol-13-acetate. J Biol Chem 274:29672-29676
64. Huang C, Li J, Song L, Zhang D, Tong Q, Ding M, Bowman L, Aziz R, Stoner GD (2006) Black raspberry extracts inhibit benzo(a)pyrene diol-epoxide-induced activator protein 1 activation and VEGF transcription by targeting the phosphatidylinositol 3-kinase/Akt pathway. Cancer Res 66:581-587
65. Huang C, Ma WY, Dong Z (1996) Requirement for phosphatidylinositol 3-kinase in epidermal growth factor-induced AP-1 transactivation and transformation in JB6 P+ cells. Mol Cell Biol 16:6427-6435
66. Huang C, Ma WY, Hecht SS, Dong Z (1997a) Inositol hexaphosphate inhibits cell transformation and activator protein 1 activation by targeting phosphatidylinositol-3' kinase. Cancer Res 57:2873-2878
67. Huang C, Ma WY, Li J, Dong Z (1999b) Arsenic induces apoptosis through a c-Jun NH2-terminal kinase-dependent, p53-independent pathway. Cancer Res 59:3053-3058
68. Huang C, Ma WY, Li J, Goranson A, Dong Z (1999c) Requirement of erk, but not JNK, for arsenite-induced cell transformation. J Biol Chem 274:14595-14601
69. Huang C, Ma WY, Young MR, Colburn N, Dong Z (1998) Shortage of mitogen-activated protein kinase is responsible for resistance to AP-1 transactivation and transformation in mouse JB6 cells. Proc Natl Acad Sci USA 95:156-161
70. Huang C, Schmid PC, Ma WY, Schmid HH, Dong Z (1997b) Phosphatidylinositol-3 kinase is necessary for 12-O-tetradecanoylphorbol-13- acetate-induced cell transformation and activated protein 1 activation. J Biol Chem 272:4187-4194
71. Huang HP, Shih YW, Chang YC, Hung CN, Wang CJ (2008) Chemoinhibitory effect of mulberry anthocyanins on melanoma metastasis involved in the ras/PI3K pathway. J Agric Food Chem 56:9286-9293
72. Huang C, Zhang D, Li J, Tong Q, Stoner GD (2007) Differential inhibition of UV-induced activation of NF kappa B and AP-1 by extracts from black raspberries, strawberries, and blueberries. Nutr Cancer 58:205-212
73. Igaki T (2009) Correcting developmental errors by apoptosis: lessons from drosophila JNK signaling. Apoptosis 14:1021-1028
74. Johansson N, Ahonen M, Kahari VM (2000) Matrix metalloproteinases in tumor invasion. Cell Mol Life Sci 57:5-15
75. Kearns JD, Hoffmann A (2009) Integrating computational and biochemical studies to explore mechanisms in NF-{kappa}B signaling. J Biol Chem 284:5439-5443
76. Khandrika L, Lieberman R, Koul S, Kumar B, Maroni P, Chandhoke R, Meacham RB, Koul HK (2009) Hypoxia-associated p38 mitogen-activated protein kinase-mediated androgen receptor activation and increased HIF-1alpha levels contribute to emergence of an aggressive phenotype in prostate cancer. Oncogene 28:1248-1260
77. Koyuturk M, Ersoz M, Altiok N (2007) Simvastatin induces apoptosis in human breast cancer cells: p53 and estrogen receptor independent pathway requiring signalling through JNK. Cancer Lett 250:220-228
78. Kuno Y, Kondo K, Iwata H, Senga T, Akiyama S, Ito K, Takagi H, Hamaguchi M (1998) Tumor-specific activation of mitogen-activated protein kinase in human colorectal and gastric carcinoma tissues. Jpn J Cancer Res 89:903-909
79. Lamy S, Beaulieu E, Labbe D, Bedard V, Moghrabi A, Barrette S, Gingras D, Beliveau R (2008) Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling. Carcinogenesis 29:1033-1041
80. Lamy S, Blanchette M, Michaud-Levesque J, Lafleur R, Durocher Y, Moghrabi A, Barrette S, Gingras D, Beliveau R (2006) Delphinidin, a dietary anthocyanidin, inhibits vascular endothelial growth factor receptor-2 phosphorylation. Carcinogenesis 27:989-996
81. Li CJ, Chang JK, Chou CH, Wang GJ, Ho ML (2010) The PI3K/Akt/FOXO3a/ p27Kip1 signaling contributes to anti-inflammatory drug-suppressed proliferation of human osteoblasts. Biochem Pharmacol 79:926-937
82. Li J, Chen H, Tang MS, Shi X, Amin S, Desai D, Costa M, Huang CPI (2004a) PI-3 K and Akt are mediators of AP-1 induction by 5-MCDE in mouse epidermal cl41 cells. J Cell Biol 165: 77-86
83. Li J, Davidson G, Huang Y, Jiang BH, Shi X, Costa M, Huang C (2004b) 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 64:94-101
84. Li J, Zhang D, Stoner GD, Huang C (2008) Differential effects of black raspberry and strawberry extracts on BaPDE-induced activation of transcription factors and their target genes. Mol Carcinog 47:286-294
85. Liu H, Liang SL, Kumar S, Weyman CM, Liu W, Zhou A (2009) Statins induce apoptosis in ovarian cancer cells through activation of JNK and enhancement of bim expression. Cancer Chemother Pharmacol 63:997-1005
86. Liu J, Lin A (2007) Wiring the cell signaling circuitry by the NF-kappa B and JNK1 crosstalk and its applications in human diseases. Oncogene 26:3267-3278
87. Liu D, Liu Z, Jiang D, Dackiw AP, Xing M (2007) Inhibitory effects of the mitogen-activated protein kinase kinase inhibitor CI-1040 on the proliferation and tumor growth of thyroid cancer cells with BRAF or RAS mutations. J Clin Endocrinol Metab 92:4686-4695
88. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 11: 32-50
89. Lu H, Li J, Zhang D, Stoner GD, Huang C (2006) Molecular mechanisms involved in chemopre-vention of black raspberry extracts: from transcription factors to their target genes. Nutr Cancer 54:69-78
90. Lu B, Shinohara ET, Edwards E, Geng L, Tan J, Hallahan DE (2005) The use of tyrosine kinase inhibitors in modifying the response of tumor microvasculature to radiotherapy. Technol Cancer Res Treat 4:691-698
91. Martiny-Baron G, Marme D (1995) VEGF-mediated tumour angiogenesis: a new target for cancer therapy. Curr Opin Biotechnol 6:675-680
92. Matheny RW Jr, Adamo ML (2009) Effects of PI3K catalytic subunit and Akt isoform deficiency on mTOR and p70S6K activation in myoblasts. Biochem Biophys Res Commun 390: 252-257
93. Mazhar D, Ang R, Waxman J (2006) COX inhibitors and breast cancer. Br J Cancer 94:346-350
94. Mazhar D, Gillmore R, Waxman J (2005) COX and cancer. Q J Med 98:711-718
95. McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Basecke J, Libra M, Stivala F, Milella M, Tafuri A, Lunghi P, Bonati A, Martelli AM (2008) Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia 22:708-722
96. Michl P, Downward J (2005) Mechanisms of disease: PI3K/AKT signaling in gastrointestinal cancers. Z Gastroenterol 43:1133-1139
97. Nabeshima K, Inoue T, Shimao Y, Sameshima T (2002) Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol Int 52:255-264
98. Ndlovu N, Van Lint C, Van Wesemael K, Callebert P, Chalbos D, Haegeman G, Vanden Berghe W (2009) Hyperactivated NF-{Kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells. Mol Cell Biol 29:5488-5504
99. Ouyang W, Li J, Ma Q, Huang C (2006) Essential roles of PI-3 k/Akt/IKKbeta/NFkappaB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells. Carcinogenesis 27:864-873
100. Ouyang W, Li J, Shi X, Costa M, Huang C (2005) Essential role of PI-3 K, ERKs and calcium signal pathways in nickel-induced VEGF expression. Mol Cell Biochem 279:35-43
101. Ouyang W, Luo W, Zhang D, Jian J, Ma Q, Li J, Shi X, Chen J, Gao J, Huang C (2008) PI-3 K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation. Environ Health Perspect 116:1-6
102. Patel RK, Mohan C (2005) PI3K/AKT signaling and systemic autoimmunity. Immunol Res 31: 47-55
103. Porter AC, Vaillancourt RR (1998) Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis. Oncogene 17:1343-1352
104. Rahmani M, Anderson A, Habibi JR, Crabtree TR, Mayo M, Harada H, Ferreira-Gonzalez A, Dent P, Grant S (2009) The BH3-only protein bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways. Blood 114:4507-4516
105. Ranson M (2002) ZD1839 (Iressa): for more than just non-small cell lung cancer. Oncologist 7(Suppl 4):16-24
106. Riely GJ (2008) Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. J Thorac Oncol 3:S146-S149
107. Robinson MJ, Cobb MH (1997) Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9:180-186
108. Rodrigo KA, Rawal Y, Renner RJ, Schwartz SJ, Tian Q, Larsen PE, Mallery SR (2006) Suppression of the tumorigenic phenotype in human oral squamous cell carcinoma cells by an ethanol extract derived from freeze-dried black raspberries. Nutr Cancer 54:58-68
109. Roux PP, Blenis J (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68:320-344
110. Schmitz KJ, Callies R, Wohlschlaeger J, Kimmig R, Otterbach F, Bohr J, Lee HS, Takeda A, Schmid KW, Baba HA (2006) Overexpression of cyclo-oxygenase-2 is an independent predictor of unfavourable outcome in node-negative breast cancer, but is not associated with protein kinase B (Akt) and mitogen-activated protein kinase (ERK1/2, p38) activation or with her-2/neu signalling pathways. J Clin Pathol 59:685-691
111. Scholtysek C, Krukiewicz AA, Alonso JL, Sharma KP, Sharma PC, Goldmann WH (2009) Characterizing components of the saw palmetto berry extract (SPBE) on prostate cancer cell growth and traction. Biochem Biophys Res Commun 379:795-798
112. Seeram NP, Momin RA, Nair MG, Bourquin LD (2001) Cyclooxygenase inhibitory and antioxi-dant cyanidin glycosides in cherries and berries. Phytomedicine 8:362-369
113. Song L, Li J, Zhang D, Liu ZG, Ye J, Zhan Q, Shen HM, Whiteman M, Huang C (2006) IKKbeta programs to turn on the GADD45alpha-MKK4-JNK apoptotic cascade specifically via p50 NF-kappaB in arsenite response. J Cell Biol 175:607-617
114. Song C, Wang W, Li M, Liu Y, Zheng D (2009) Tax1 enhances cancer cell proliferation via ras-raf-MEK-ERK signaling pathway. IUBMB Life 61:685-692
115. Sun W, Wang Q, Chen B, Liu J, Liu H, Xu W (2008) Gamma-tocotrienol- induced apoptosis in human gastric cancer SGC-7901 cells is associated with a suppression in mitogen-activated protein kinase signalling. Br J Nutr 99:1247-1254
116. Sun Y, Yang T, Xu Z (2007) The JNK pathway and neuronal migration. J Genet Genomics 34: 957-965
117. Sweeney SE, Firestein GS (2006) Mitogen activated protein kinase inhibitors: where are we now and where are we going? Ann the Rheum Dis 65(Suppl 3):iii83-88
118. Taruscio TG, Barney DL, Exon J (2004) Content and profile of flavanoid and phenolic acid compounds in conjunction with the antioxidant capacity for a variety of northwest vaccinium berries. J Agric Food Chem 52:3169-3176
119. Teller N, Thiele W, Marczylo TH, Gescher AJ, Boettler U, Sleeman J, Marko D (2009) Suppression of the kinase activity of receptor tyrosine kinases by anthocyanin-rich mixtures extracted from bilberries and grapes. J Agric Food Chem 57:3094-3101
120. Tian Q, Giusti MM, Stoner GD, Schwartz SJ (2006) Urinary excretion of black raspberry (rubus occidentalis) anthocyanins and their metabolites. J Agric Food Chem 54: 1467-1472
121. Uranga RM, Giusto NM, Salvador GA (2009) Iron-induced oxidative injury differentially regulates PI3K/Akt/GSK3beta pathway in synaptic endings from adult and aged rats. Toxicol Sci 111:331-344
122. Verstrepen L, Carpentier I, Verhelst K, Beyaert R (2009) ABINs: A20 binding inhibitors of NF-kappa B and apoptosis signaling. Biochem Pharmacol 78:105-114
123. Von Pawel J (2004) Gefitinib (Iressa, ZD1839): a novel targeted approach for the treatment of solid tumors. Bull Cancer 91:E70-E76
124. Wagner EF, Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev 9:537-549
125. Wang SY, Feng R, Bowman L, Lu Y, Ballington JR, Ding M (2007) Antioxidant activity of vac-cinium stamineum: exhibition of anticancer capability in human lung and leukemia cells. Planta Med 73:451-460
126. Wang LS, Hecht SS, Carmella SG, Yu N, Larue B, Henry C, McIntyre C, Rocha C, Lechner JF, Stoner GD (2009) Anthocyanins in black raspberries prevent esophageal tumors in rats. Cancer Prev Res 2:84-93
127. Wang J, Ouyang W, Li J, Wei L, Ma Q, Zhang Z, Tong Q, He J, Huang C (2005) Loss of tumor suppressor p53 decreases PTEN expression and enhances signaling pathways leading to activation of activator protein 1 and nuclear factor kappaB induced by UV radiation. Cancer Res 65:6601-6611
128. Wang LS, Stoner GD (2008) Anthocyanins and their role in cancer prevention. Cancer Lett 269:281-290
129. Wang X, Zhang X, Cheng Y, Li C, Zhang W, Liu L, Ding Z (2010) Alpha-lipoic acid prevents bupivacaine-induced neuron injury in vitro through a PI3K/Akt-dependent mechanism. Neurotoxicology 31:101-112
130. Wei X, Guo W, Wu S, Wang L, Lu Y, Xu B, Liu J, Fang B (2009) Inhibiting JNK dephosphorylation and induction of apoptosis by novel anticancer agent NSC-741909 in cancer cells. J Biol Chem 284:16948-16955
131. Whyte J, Bergin O, Bianchi A, McNally S, Martin F (2009) Key signalling nodes in mammary gland development and cancer. Mitogen-Activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development. Breast Cancer Res 11:209
132. Widmann C, Gibson S, Jarpe MB, Johnson GL (1999) Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 79:143-180
133. Williams C, Shattuck-Brandt RL, DuBois RN (1999) The role of COX-2 in intestinal cancer. Ann N Y Acad Sci 889:72-83
134. Wu GS (2007) Role of mitogen-activated protein kinase phosphatases (MKPs) in cancer. Cancer Metastasis Rev 26:579-585
135. Xiao W, Yang Y, Weng Q, Lin T, Yuan M, Yang K, Pang Y (2009) The role of the PI3K-Akt signal transduction pathway in autographa californica multiple nucleopolyhedrovirus infection of spodoptera frugiperda cells. Virology 391:83-89
136. Xie D, Gore C, Zhou J, Pong RC, Zhang H, Yu L, Vessella RL, Min W, Hsieh JT (2009) DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis. Proc Natl Acad Sci USA 106:19878-19883
137. Xu C, Shen G, Yuan X, Kim JH, Gopalkrishnan A, Keum YS (2006) Kong AN ERK and JNK signaling pathways are involved in the regulation of activator protein 1 and cell death elicited by three isothiocyanates in human prostate cancer PC-3 cells. Carcinogenesis 27:437-445
138. Xue H, Aziz RM, Sun N, Cassady JM, Kamendulis LM, Xu Y, Stoner GD, Klaunig JE (2001) Inhibition of cellular transformation by berry extracts. Carcinogenesis 22:351-356
139. Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS, Workman P (2008) Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 8:393-412
140. Yu Y, Wan Y, Huang C (2009) The biological functions of NF-kappaB1 (p50) and its potential as an anti-cancer target. Curr Cancer Drug Targets 9:566-571
141. Yu JH, Wang HJ, Li XR, Tashiro S, Onodera S, Ikejima T (2008) Protein tyrosine kinase, JNK, and ERK involvement in pseudolaric acid B-induced apoptosis of human breast cancer MCF-7 cells. Acta Pharmacol Sin 29:1069-1076
142. Yun JM, Afaq F, Khan N, Mukhtar H (2009) Delphinidin, an anthocyanidin in pigmented fruits and vegetables, induces apoptosis and cell cycle arrest in human colon cancer HCT116 cells. Mol Carcinog 48:260-270
143. Zhang D, Li J, Costa M, Gao J, Huang C (2010) JNK1 mediates degradation HIF-1alpha by a VHL-independent mechanism that involves the chaperones hsp90/hsp70. Cancer Res 70: 813-823
144. Zhang GX, Lu XM, Kimura S, Nishiyama A (2007) Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation. Cardiovasc Res 76:204-212
145. Zheng G, Chen Y, Zhang X, Cai T, Liu M, Zhao F, Luo W, Chen J (2008) Acute cold exposure and rewarming enhanced spatial memory and activated the MAPK cascades in the rat brain. Brain Res 1239:171-180
146. Zhou HY, Pon YL, Wong AS (2007a) Synergistic effects of epidermal growth factor and hepatocyte growth factor on human ovarian cancer cell invasion and migration: role of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. Endocrinology 148:5195-5208
147. Zhou HY, Wan KF, Ip CK, Wong CK, Mak NK, Lo KW, Wong AS (2008) Hepatocyte growth factor enhances proteolysis and invasiveness of human nasopharyngeal cancer cells through activation of PI3K and JNK. FEBS Lett 582:3415-3422
148. Zhou YJ, Yang HW, Wang XG, Zhang H (2009b) Hepatocyte growth factor prevents advanced gly-cation end products-induced injury and oxidative stress through a PI3K/Akt-dependent pathway in human endothelial cells. Life Sci 85:670-677
149. Zhou Y, Yau C, Gray JW, Chew K, Dairkee SH, Moore DH, Eppenberger U, Eppenberger-Castori S, Benz CC (2007b) Enhanced NF kappa B and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer 7:59
150. Zhou Y, Zhen H, Mei Y, Wang Y, Feng J, Xu S, Fu X (2009a) PI3K/AKT mediated p53 down-regulation participates in CpG DNA inhibition of spontaneous B cell apoptosis. Cell Mol Immunol 6:175-180
151. Zureikat AH, McKee MD (2008) Targeted therapy for solid tumors: current status. Surg Oncol Clin N Am 17:279-301
152. Zwick E, Bange J, Ullrich A (2001) Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr Relat Cancer 8:161-173