Activation of the PI3K/Akt pathway and chemotherapeutic resistance

Drug Resistance Updates

Volumn 5, Issue 6, 2002, Pages 234-248

  West, Kip A ^a   Castillo, S Sianna ^a   Dennis, Phillip A ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

Author keywords

Akt; Apoptosis; Cancer; Chemotherapy; Kinase

Indexed keywords

2 [[2 [[2 [(2 AMINO 3 MERCAPTOPROPYL)AMINO] 3 METHYLPENTYL]OXY] 1 OXO 3 PHENYLPROPYL]AMINO] 4 (METHYLSULFONYL)BUTANOIC ACID ISOPROPYL ESTER; 2 MORPHOLINO 8 PHENYLCHROMONE; 7 HYDROXYSTAUROSPORINE; ANTHRACYCLINE DERIVATIVE; ANTINEOPLASTIC AGENT; BUTYRIC ACID; CISPLATIN; DAUNORUBICIN; DNA TOPOISOMERASE INHIBITOR; DOXORUBICIN; ETOPOSIDE; FR 901228; GEFITINIB; GEMCITABINE; IMATINIB; LAPATINIB; MIDOSTAURIN; N [[5 [(2 AMINO 3 MERCAPTOPROPYL)AMINO][1,1' BIPHENYL] 2 YL]CARBONYL]METHIONINE METHYL ESTER; NUCLEOSIDE ANALOG; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B; STAUROSPORINE; TAMOXIFEN; TEMSIROLIMUS; TOPOTECAN; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; WORTMANNIN;

CANCER; CANCER COMBINATION CHEMOTHERAPY; CANCER RESISTANCE; CARCINOGENESIS; CELL FUNCTION; CELL SURVIVAL; DRUG EFFICACY; ENZYME ACTIVATION; ENZYME REGULATION; METASTASIS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; ANTINEOPLASTIC AGENTS; DRUG RESISTANCE, NEOPLASM; ENZYME ACTIVATION; ENZYME INHIBITORS; HUMANS; NEOPLASMS; ONCOGENE PROTEIN V-AKT; RETROVIRIDAE PROTEINS, ONCOGENIC;

EID: 0036968347     PISSN: 13687646     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1368-7646(02)00120-6     Document Type: Review

References (148)

1. Ackler, S., Ahmad, S., Tobias, C., Johnson, M.D., Glazer, R.I., 2002. Delayed mammary gland involution in MMTV-AKT1 transgenic mice. Oncogene 21, 198-206.
2. Albers, M.W., Williams, R.T., Brown, E.J., Tanaka, A., Hall, F.L., Schreiber, S.L., 1993. FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line. J. Biol. Chem. 268, 22825-22829.
3. Alkan, S., Izban, K.F., 2002. Immunohistochemical localization of phosphorylated AKT in multiple myeloma. Blood 99, 2278-2279.
4. Anderson, N.G., Ahmad, T., Chan, K., Dobson, R., Bundred, N.J., 2001. ZD1839 (Iressa), a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression. Int. J. Cancer 94, 774-782.
5. Asselin, E., Mills, G.B., Tsang, B.K., 2001. XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer Res. 61, 1862-1868.
6. Bellacosa, A., Testa, J.R., Staal, S.P., Tsichlis, P.N., 1991. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254, 274-277.
7. Blume-Jensen, P., Hunter, T., 2001. Oncogenic kinase signalling. Nature 411, 355-365.
8. Bonser, R.W., Thompson, N.T., Randall, R.W., Tateson, J.E., Spacey, G.D., Hodson, H.F., Garland, L.G., 1991. Demethoxyviridin and wortmannin block phospholipase C and D activation in the human neutrophil. Br. J. Pharmacol. 103, 1237-1241.
9. Boulton, S., Kyle, S., Durkacz, B.W., 2000. Mechanisms of enhancement of cytotoxicity in etoposide and ionising radiation-treated cells by the protein kinase inhibitor wortmannin. Eur. J. Cancer 36, 535-541.
10. Boulton, S., Kyle, S., Yalcintepe, L., Durkacz, B.W., 1996. Wortmannin is a potent inhibitor of DNA double strand break but not single strand break repair in Chinese hamster ovary cells. Carcinogenesis 17, 2285-2290.
11. Braun-Dullaeus, R.C., Mann, M.J., Seay, U., Zhang, L., von Der Leyen, H.E., Morris, R.E., Dzau, V.J., 2001. Cell cycle protein expression in vascular smooth muscle cells in vitro and in vivo is regulated through phosphatidylinositol 3-kinase and mammalian target of rapamycin. Arterioscler. Thromb. Vasc. Biol. 21, 1152-1158.
12. Brognard, J., Clark, A.S., Ni, Y., Dennis, P.A., 2001. Akt/protein kinase b is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res. 61, 3986-3997.
13. Brognard, J., West, K., Clark, A.S., Linnoila, R.I., Yang, X., Swain, S., Harris, C.C., Belinsky, S., Dennis, P.A., 2002. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J. Clin. Invest., in press.
14. Brunn, G.J., Williams, J., Sabers, C., Wiederrecht, G., Lawrence, Jr., J.C., Abraham, R.T., 1996. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J. 15, 5256-5267.
15. Cantley, L.C., 2002. The phosphoinositide 3-kinase pathway. Science 296, 1655-1657.
16. Casagrande, F., Bacqueville, D., Pillaire, M.J., Malecaze, F., Manenti, S., Breton-Douillon, M., Darbon, J.M., 1998. G1 phase arrest by the phosphatidylinositol 3-kinase inhibitor LY 294002 is correlated to up-regulation of p27Kip1 and inhibition of G1 CDKs in choroidal melanoma cells. FEBS Lett. 422, 385-390.
17. Chen, E.Y., Mazure, N.M., Cooper, J.A., Giaccia, A.J., 2001. Hypoxia activates a platelet-derived growth factor receptor/phosphatidylinositol 3-kinase/Akt pathway that results in glycogen synthase kinase-3 inactivation. Cancer Res. 61, 2429-2433.
18. Cheng, J.Q., Jiang, X., Fraser, M., Li, M., Dan, H.C., Sun, M., Tsang, B.K., 2002. Role of X-linked inhibitor of apoptosis protein in chemoresistance in ovarian cancer: possible involvement of the phophoinositide-3 kinase pathway. Drug. Resist. Updates 5, 131-146.
19. Chinni, S.R., Sarkar, F.H., 2002. Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells. Clin. Cancer Res. 8, 1228-1236.
20. Clark, A.E., West, K., Streicher, S., Dennis, P.A., 2002. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, and tamoxifen in breast cancer cells. Mol. Cancer Ther. 1, 707-717.
21. Coffer, P.J., Woodgett, J.R., 1991. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families [published erratum appears in Eur. J. Biochem. May 1, 1992;205(3):1217]. Eur. J. Biochem. 201, 475-481.
22. Cross, D., Alessi, D., Cohen, P., Andjelkovich, M., Hemmings, B., 1995a. Inhibition of glycogen synthase kinase-3 by insuylin mediated by protein kinase B. Nature 378, 785-789.
23. Cross, M.J., Stewart, A., Hodgkin, M.N., Kerr, D.J., Wakelam, M.J., 1995b. Wortmannin and its structural analogue demethoxyviridin inhibit stimulated phospholipase A2 activity in Swiss 3T3 cells. Wortmannin is not a specific inhibitor of phosphatidylinositol 3-kinase. J. Biol. Chem. 270, 25352-25355.
24. Crossthwaite, A.J., Hasan, S., Williams, R.J., 2002. Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca(2+) and PI3-kinase. J. Neurochem. 80, 24-35.
25. Crul, M., Rosing, H., de Klerk, G.J., Dubbelman, R., Traiser, M., Reichert, S., Knebel, N.G., Schellens, J.H., Beijnen, J.H., ten Bokkel Huinink, W.W., 2002. Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur. J. Cancer 38, 1615-1621.
26. Cuello, M., Ettenberg, S.A., Clark, A.S., Keane, M.M., Posner, R.H., Nau, M.M., Dennis, P.A., Lipkowitz, S., 2001. Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res. 61, 4892-4900.
27. Datta, S.R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., Greenberg, M.E., 1997. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231-241.
28. Datta, S.R., Brunet, A., Greenberg, M.E., 1999. Cellular survival: a play in three Akts. Genes Dev. 13, 2905-2927.
29. Davies, S.P., Reddy, H., Caivano, M., Cohen, P., 2000. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95-105.
30. Del Bufalo, D., Di Castro, V., Biroccio, A., Varmi, M., Salani, D., Rosano, L., Trisciuoglio, D., Spinella, F., Bagnato, A., 2002. Endothelin-1 protects ovarian carcinoma cells against paclitaxel-induced apoptosis: requirement for Akt activation. Mol. Pharmacol. 61, 524-532.
31. del Peso, L., Gonzalez-Garcia, M., page, C., Herrera, R., Nunez, G., 1997. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278, 687-689.
32. Di Cristofano, A., Kotsi, P., Peng, Y.F., Cordon-Cardo, C., Elkon, K.B., Pandolfi, P.P., 1999. Impaired fas response and autoimmunity in Pten± mice. Science 285, 2122-2125.
33. Diehl, J.A., Cheng, M., Roussel, M.E., Sherr, C.J., 1998. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499-3511.
34. Dierov, J., Xu, Q., Dierova, R., Carroll, M., 2002. TEL/platelet-derived growth factor receptor beta activates phosphatidylinositol 3 (PI3) kinase and requires PI3 kinase to regulate the cell cycle. Blood 99, 1758-1765.
35. Du, K., Montminy, M., 1998. CREB is a regulatory target for the protein kinase Akt/PKB. J. Biol. Chem. 273, 32377-32379.
36. Dudkin, L., Dilling, M.B., Cheshire, P.J., Harwood, F.C., Hollingshead, M., Arbuck, S.G., Travis, R., Sausville, E.A., Houghton, P.J., 2001. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin. Cancer Res. 7, 1758-1764.
37. Edwards, E., Geng, L., Tan, J., Onishko, H., Donnelly, E., Hallahan, D.E., 2002. Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Res. 62, 4671-4677.
38. Egorin, M.J., Parise, R.A., Joseph, E., Hamburger, D.R., Lan, J., Covey, J.M., Eiseman, J.L., 2002. Plasma pharmacokinetics and bioavailablility for the phosphatidylinositide-3-kinase signalling inhibitor, OMDPI (NSC 710297) in CD2F1 mice. Proc. Am. Assoc. Cancer Res. 43, 604.
39. Fang, G., Kim, C.N., Perkins, C.L., Ramadevi, N., Winton, E., Wittmann, S., Bhalla, K.N., 2000. CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs. Blood 96, 2246-2253.
40. Fecteau, K.A., Mei, J., Wang, H.C., 2002. Differential modulation of signaling pathways and apoptosis of ras-transformed 10T1/2 cells by the depsipeptide FR901228. J. Pharmacol. Exp. Ther. 300, 890-899.
41. Fingar, D.C., Salama, S., Tsou, C., Harlow, E., Blenis, J., 2002. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBPI/eIF4E. Genes Dev. 16, 1472-1487.
42. Geoerger, B., Kerr, K., Tang, C.B., Fung, K.M., Powell, B., Sutton, L.N., Phillips, P.C., Janss, A.J., 2001. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res. 61, 1527-1532.
43. Guo, M., Joiakim, A., Reiners, J.J., 2000. Suppression of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated aryl hydrocarbon receptor transformation and CYP1A1 induction by the phosphatidylinositol 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). Biochem. Pharmacol. 60, 635-642.
44. Gupta, A.K., McKenna, W.G., Weber, C.N., Feldman, M.D., Goldsmith, J.D., Mick, R., Machtay, M., Rosenthal, D.I., Bakanauskas, V.J., Cemiglia, G.J., Bernhard, E.J., Weber, R.S., Muschel, R.J., 2002. Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin. Cancer Res. 8, 885-892.
45. Hayakawa, J., Ohmichi, M., Tasaka, K., Kanda, Y., Adachi, K., Nishio, Y., Hisamoto, K., Mabuchi, S., Hinuma, S., Murata, Y., 2002. Regulation of the PRL promoter by Akt through cAMP response element binding protein. Endocrinology 143, 13-22.
46. Helgason, C.D., Damen, J.E., Rosten, P., Grewal, R., Sorensen, P., Chappel, S.M., Borowski, A., Jirik, F., Krystal, G., Humphries, R.K., 1998. Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev. 12, 1610-1620.
47. Hidalgo, M., Rowinsky, E.K., 2000. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 19, 6680-6686.
48. Hilgard, P., Klenner, T., Stekar, J., Nossner, G., Kutscher, B., Engel, J., 1997. D-21266, a new heterocyclic alkylphospholipid with antitumour activity. Eur. J. Cancer 33, 442-446.
49. Hill, M., Hemmings, B., 2002. Inhibition of protein kinase B/Akt. Implications for cancer therapy. Pharmacol. Ther. 93, 243.
50. Holland, E.C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R.E., Fuller, G.N., 2000. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat. Genet. 25, 55-57.
51. Hosoi, H., Dilling, M.B., Shikata, T., Liu, L.N., Shu, L., Ashmun, R.A., Germain, G.S., Abraham, R.T., Houghton, P.J., 1999. Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res. 59, 886-894.
52. Hsu, J., Shi, Y., Krajewski, S., Renner, S., Fisher, M., Reed, J.C., Franke, T.F., Lichtenstein, A., 2001. The AKT kinase is activated in multiple myeloma tumor cells. Blood 98, 2853-2855.
53. Hu, L., Zaloudek, C., Mills, G.B., Gray, J., Jaffe, R.B., 2000a. In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin. Cancer Res. 6, 880-886.
54. Hu, Y., Qiao, L., Wang, S., Rong, S., Meuillet, E.J., Berggren, M., Gallegos, A., Powis, G., Kozikowski, A.P., 2000b. 3-(Hydroxymethyl)-bearing phosphatidylinositol ether lipid analogues and carbonate surrogates block PI3-K, akt, and cancer cell growth. J. Med. Chem. 43, 3045-3051.
55. Hu, Y., Meuillet, E.J., Berggren, M., Powis, G., Kozikowski, A.P., 2001. 3-Deoxy-3-substituted-D-myo-inositol imidazolyl ether lipid phosphates and carbonate as inhibitors of the phosphatidylinositol 3-kinase pathway and cancer cell growth. Bioorg. Med. Chem. Lett. 11, 173-176.
56. Hu, L., Hofmann, J., Lu, Y., Mills, G.B., Jaffe, R.B., 2002. Inhibition of phosphatidylinositol 3′-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res. 62, 1087-1092.
57. Huang, S., Houghton, P.J., 2001. Mechanisms of resistance to rapamycins. Drug Resist. Updates 4, 378-391.
58. Hutchinson, J., Jin, J., Cardiff, R.D., Woodgett, J.R., Muller, W.J., 2001. Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression. Mol. Cell. Biol. 21, 2203-2212.
59. Itoh, N., Semba, S., Ito, M., Takeda, H., Kawata, S., Yamakawa, M., 2002. Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer 94, 3127-3134.
60. Jiang, K., Coppola, D., Crespo, N.C., Nicosia, S.V., Hamilton, A.D., Sebti, S.M., Cheng, J.Q., 2000. The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol. Cell. Biol. 20, 139-148.
61. Jones, P.F., Jakubowicz, T., Pitossi, F.J., Maurer, F., Hemmings, B.A., 1991. Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc. Natl. Acad. Sci. U.S.A. 88, 4171-4175.
62. Jones, R.G., Parsons, M., Bonnard, M., Chan, V.S., Yeh, W.C., Woodgett, J.R., Ohashi, P.S., 2000. Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and Bcl-X(L) levels in vivo. J. Exp. Med. 191, 1721-1734.
63. Kanamori, Y., Kigawa, J., Itamochi, H., Shimada, M., Takahashi, M., Kamazawa, S., Sato, S., Akeshima, R., Terakawa, N., 2001. Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma. Clin. Cancer Res. 7, 892-895.
64. Kandel, E.S., Hay, N., 1999. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp. Cell Res. 253, 210-229.
65. Katso, R., Okkenhaug, K., Ahmadi, K., White, S., Timms, J., Waterfield, M.D., 2001. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Ann. Rev. Cell Dev. Biol. 17, 615-675.
66. Kim, S.H., Um, J.H., Dong-Won, B., Kwon, B.H., Kim, D.W., Chung, B.S., Kang, C.D., 2000. Potentiation of chemosensitivity in multidrug-resistant human leukemia CEM cells by inhibition of DNA-dependent protein kinase using wortmannin. Leuk. Res. 24, 917-925.
67. Kim, A.H., Khursigara, G., Sun, X., Franke, T.F., Chao, M.V., 2001. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol. Cell Biol. 21, 893-901.
68. Klein, R.D., Fischer, S.M., 2002. Black tea polyphenols inhibit IGF-I-induced signaling through Akt in normal prostate epithelial cells and Du145 prostate carcinoma cells. Carcinogenesis 23, 217-221.
69. Klejman, A., Rushen, L., Morrione, A., Slupianek, A., Skorski, T., 2002. Phosphatidylinositol-3 kinase inhibitor enhance the anti-leukemia effect of STI571. Oncogene 21, 5868-5876.
70. Kozikowski, A.P., Sun, H., Brognard, J., Dennis, P.A., 2002. Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase, Akt (in press).
71. Krystal, G.W., Sulanke, G., Litz, J., 2002. Inhibition of phosphatidylinositol 3-kinase-Akt signaling blocks growth, promotes apoptosis, and enhances sensitivity of small cell lung cancer cells to chemotherapy. Mol. Cancer Ther. 1, 913-922.
72. Kurose, K., Zhou, X.P., Araki, T., Cannistra, S.A., Maher, E.R., Eng, C., 2001. Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas. Am. J. Pathol. 158, 2097-2106.
73. Lawlor, M.A., Alessi, D.R., 2001. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J. Cell Sci. 114, 2903-2910.
74. Lemke, L.E., Paine-Murrieta, G.D., Taylor, C.W., Powis, G., 1999. Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase. Cancer Chemother. Pharmacol. 44, 491-497.
75. Leslie, N.R., Biondi, R.M., Alessi, D.R., 2001. Phosphoinositide-regulated kinases and phosphoinositide phosphatases. Chem. Rev. 101, 2365-2380.
76. Liang, J., Zubovitz, J., Petrocelli, T., Kotchetkov, R., Connor, M.K., Han, K., Lee, J.H., Ciarallo, S., Catzavelos, C., Beniston, R., Frinssen, E., Slingerland, J.M., 2002. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat. Med. 8, 1153-1160.
77. Liu, Q., Sasaki, T., Kozieradzki, I., Wakeham, A., Itie, A., Dumont, D.J., Penninger, J.M., 1999. SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival. Genes Dev. 13, 786-791.
78. Ma, N., Jin, J., Lu, F., Woodgett, J., Liu, F.F., 2001. The role of protein kinase B (PKB) in modulating heat sensitivity in a human breast cancer cell line. Int. J. Radiat. Oncol. Biol. Phys. 50, 1041-1050.
79. Mabuchi, S., Ohmichi, M., Kimura, A., Hisamoto, K., Hayakawa, J., Nishio, Y., Adachi, K., Takahashi, K., Arimoto-Ishida, E., Nakatsuji, Y., Tasaka, K., Murata, Y., 2002. Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. J. Biol. Chem. 277, 33490-33500.
80. Maira, S.M., Galetic, I., Brazil, D.P., Kaech, S., Ingley, E., Thelen, M., Hemmings, B.A., 2001. Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science 294, 374-380.
81. Malik, S.N., Brattain, M., Ghosh, P.M., Troyer, D.A., Prihoda, T., Bedolla, R., Kreisberg, J.I., 2002. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin. Cancer Res. 8, 1168-1171.
82. Malstrom, S., Tili, E., Kappes, D., Ceci, J.D., Tsichlis, P.N., 2001. Tumor induction by an Lck-MyrAkt transgene is delayed by mechanisms controlling the size of the thymus. Proc. Natl. Acad. Sci. U.S.A. 98, 14967-14972.
83. Martindale, J.L., Holbrook, N.J., 2002. Cellular response to oxidative stress: signaling for suicide and survival. J. Cell Physiol. 192, 1-15.
84. Medema, R.H., Kops, G.J., Bos, J.L., Burgering, B.M., 2000. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kipl. Nature 404, 782-787.
85. Moasser, M.M., Basso, A., Averbuch, S.D., Rosen, N., 2001. The tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res. 61, 7184-7188.
86. Moorehead, R.A., Fata, J.E., Johnson, M.B., Khokha, R., 2001. Inhibition of mammary epithelial apoptosis and sustained phosphorylation of Akt/PKB in MMTV-IGF-II transgenic mice. Cell Death Differ. 8, 16-29.
87. Nakanishi, S., Kakita, S., Takahashi, I., Kawahara, K., Tsukuda, E., Sano, T., Yamada, K., Yoshida, M., Kase, H., Matsuda, Y., et al., 1992. Wortmannin, a microbial product inhibitor of myosin light chain kinase. J. Biol. Chem. 267, 2157-2163.
88. Nakashio, A., Fujita, N., Rokudai, S., Sato, S., Tsuruo, T., 2000. Prevention of phosphatidylinositol 3′-kinase-Akt survival signaling pathway during topotecan-induced apoptosis. Cancer Res. 60, 303-5309.
89. Nakayama, H., Ikebe, T., Beppu, M., Shirasuna, K., 2001. High expression levels of nuclear factor kappaB, IkappaB kinase alpha and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer 92, 3037-3044.
90. Nave, B.T., Ouwens, M., Withers, D.J., Alessi, D.R., Shepherd, P.R., 1999. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 344 (Pt 2), 427-431.
91. Nelson, J.M., Fry, D.W., 2001. Akt, MAPK (Erk1/2), and p38 Act in concert to promote apoptosis in response to ErbB receptor family inhibition. J. Biol. Chem. 276, 14842-14847.
92. Neshat, M.S., Mellinghoff, I.K., Tran, C., Stiles, B., Thomas, G., Petersen, R., Frost, P., Gibbons, J.J., Wu, H., Sawyers, C.L., 2001. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl. Acad. Sci. U.S.A. 98, 10314-10319.
93. Ng, S.S.W., Tsao, M.S., Chow, S., Hedley, D.W., 2000. Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res. 60, 5451-5455.
94. Ng, S.S., Tsao, M.S., Nicklee, T., Hedley, D.W., 2001. Wortmannin inhibits pkb/akt phosphorylation and promotes gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin. Cancer Res. 7, 3269-3275.
95. Nicholson, K.M., Anderson, N.G., 2002. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14, 381-395.
96. Normanno, N., Campiglio, M., De, L.A., Somenzi, G., Maiello, M., Ciardiello, F., Gianni, L., Salomon, D.S., Menard, S., 2002. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann. Oncol. 13, 65-72.
97. Orsulic, S., Li, Y., Soslow, R.A., Vitale-Cross, L.A., Gutkind, J.S., Varmus, H.E., 2002. Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell 1, 53-62.
98. Ouyang, Y.B., Zhang, X.H., He, Q.P., Wang, G.X., Siesjo, B.K., Hu, B.R., 2000. Differential phosphorylation at Ser473 and Thr308 of Akt-1 in rat brain following hypoglycemic coma. Brain Res. 876, 191-195.
99. Ozes, O.N., Mayo, L.D., Gustin, J.A., Pfeffer, S.R., Pfeffer, L.M., Donner, D.B., 1999. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401, 82-85.
100. Parsons, M.J., Jones, R.G., Tsao, M.S., Odermatt, B., Ohashi, P.S., Woodgett, J.R., 2001. Expression of active protein kinase b in t cells perturbs both t and b cell homeostasis and promotes inflammation. J. Immunol. 167, 42-48.
101. Patel, V., Lahusen, T., Sy, T., Sausville, E.A., Gutkind, J.S., Senderowicz, A.M., 2002. Perifosine, a novel alkylphospholipid, induces p21 (WAF1) expression in squamous carcinoma cells through a p53-independent pathway, leading to loss in cyclin-dependent kinase activity and cell cycle arrest. Cancer Res. 62, 1401-1409.
102. Pianetti, S., Guo, S., Kavanagh, K.T., Sonenshein, G.E., 2002. Green tea polyphenol epigallocatechin-3 gallate inhibits Her-2/neu signaling, proliferation, and transformed phenotype of breast cancer cells. Cancer Res. 62, 652-655.
103. Plo, I., Bettaieb, A., Payrastre, B., Mansat-De Mas, V., Bordier, C., Rousse, A., Kowalski-Chauvel, A., Laurent, G., Lautier, D., 1999. The phosphoinositide 3-kinase/Akt pathway is activated by daunorubicin in human acute myeloid leukemia cell lines. FEBS Lett, 452, 150-154.
104. Podsypanina, K., Lee, R.T., Politis, C., Hennessy, I., Crane, A., Puc, J., Neshat, M., Wang, H., Yang, L., Gibbons, J., Frost, P., Dreisbach, V., Blenis, J., Gaciong, Z., Fisher, P., Sawyers, C., Hedrick-Ellenson, L., Parsons, R., 2001. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice. Proc. Natl. Acad. Sci. U.S.A. 98, 10320-10325.
105. Powis, G., Bonjouklian, R., Berggren, M.M., Gallegos, A., Abraham, R., Ashendel, C., Zalkow, L., Matter, W.F., Dodge, J., Grindey, G., et al., 1994. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res. 54, 2419-2423.
106. Qiao, L., Nan, F., Kunkel, M., Gallegos, A., Powis, G., Kozikowski, A.P., 1998. 3-Deoxy-D-myo-inositol 1-phosphate, 1-phosphonate, and ether lipid analogues as inhibitors of phosphatidylinositol-3-kinase signaling and cancer cell growth. J. Med. Chem. 41, 3303-3306.
107. Romashkova, J.A., Makarov, S.S., 1999, NF-KB is a target of AKT in anti-apoptotic PDGF signalling, Nature 401, 86-90.
108. Rong, S.B., Hu, Y., Enyedy, I., Powis, G., Meuillet, E.J., Wu, X., Wang, R., Wang, S., Kozikowski, A.P., 2001, Molecular modeling studies of the Akt PH domain and its interaction with phosphoinositides. J. Med. Chem. 44, 898-908.
109. Rosenzweig, K.E., Youmell, M.B., Palayoor, S.T., Price, B.D., 1997. Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. Clin. Cancer Res. 3, 1149-1156.
110. Roy, H.K., Olusola, B.F., Clemens, D.L., Karolski, W.J., Ratashak, A., Lynch, H.T., Smyrk, T.C., 2002. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 23, 201-205.
111. Sakurai, M., Hayashi, T., Abe, K., Itoyuama, Y., Tabayashi, K., 2001. Induction of phosphatidylinositol 3-kinase and serine-threonine kinase-like immunoreactivity in rabbit spinal cord after transient ischemia. Neurosci. Lett. 302, 17-20.
112. Salomon, D.S., Brandt, R., Ciardiello, F., Normanno, N., 1995. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit. Rev. Oncol. Hematol. 19, 183-232.
113. Sanchez-Margalet, V., Goldfine, I.D., Vlahos, C.J., Sung, C.K., 1994. Role of phosphatidylinositol-3-kinase in insulin receptor signaling: studies with inhibitor, LY294002. Biochem. Biophys. Res. Commun. 204, 446-452.
114. Sarkaria, J.N., Tibbetts, R.S., Busby, E.C., Kennedy, A.P., Hill, D.E., Abraham, R.T., 1998. Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res. 58, 4375-4382.
115. Sato, S., Fujita, N., Tsuruo, T., 2002a. Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 21, 1727-1738.
116. Sato, T., Koike, L., Miyata, Y., Hirata, M., Mimaki, Y., Sashida, Y., Yano, M., Ito, A., 2002b. Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metalloproteinases-1 production and suppression of production of matrix metalloproteinases-1 and -9 in human fibrosarcoma HT-1080 cells. Cancer Res. 62, 1025-1029.
117. Schmelzle, T., Hall, M.N., 2000. TOR, a central controller of cell growth. Cell 103, 253-262.
118. Schultz, R.M., Merriman, R.L., Andis, S.L., Bonjouklian, R., Grindey, G.B., Rutherford, P.G., Gallegos, A., Massey, K., Powis, G., 1995. In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res. 15, 1135-1139.
119. Segrelles, C., Ruiz, S., Perez, P., Murga, C., Santos, M., Budunova, I.V., Martinez, J., Larcher, F., Slaga, T.J., Gutkind, J.S., Jorcano, J.L., Paramio, J.M., 2002. Functional roles of Akt signaling in mouse skin tumorigenesis. Oncogene 21, 53-64.
120. Sekulic, A., Hudson, C.C., Homme, J.L., Yin, P., Otterness, D.M., Karnitz, L.M., Abraham, R.T., 2000. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60, 3504-3513.
121. Semba, S., Itoh, N., Ito, M., Harada, M., Yamakawa, M., 2002. The in vitro and in vivo effects of 2-(4-morpholinyl)-8-phenyl-chromone (LY294002), a specific inhibitor of phosphatidylinositol 3′-kinase, in human colon cancer cells. Clin. Cancer Res. 8, 1957-1963.
122. Seufferlein, T., Rozengurt, E., 1996. Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res. 56, 3895-3897.
123. Shaw, M., Cohen, P., Alessi, D.R., 1998. The activation of protein kinase B by H202 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. Biochem. J. 336, 241-246.
124. Shi, Y., Gera, J., Hu, L., Hsu, J.H., Bookstein, R., Li, W., Lichtenstein, A., 2002. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res. 62, 5027-5034.
125. Shin, I., Yakes, F.M., Rojo, F., Shin, N.Y., Bakin, A.V., Baselga, J., Arteaga, C.L., 2002. PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization. Nat. Med. 8, 1145-1152.
126. Stocker, H., Andjelkovic, M., Oldham, S., Laffargue, M., Wymann, M.P., Hemmings, B.A., Hafen, E., 2002. Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science 295, 2088-2091.
127. Sun, M., Wang, G., Paciga, J.E., Feldman, R.I., Yuan, Z.Q., Ma, X.L., Shelly, S.A., Jove, R., Tsichlis, P.N., Nicosia, S.V., Cheng, J.Q., 2001. AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncongenic transformation in NIH3T3 cells. Am. J. Pathol. 159, 431-437.
128. Tang, D., Okada, H., Ruland, J., Liu, L., Stambolic, V., Mak, T.W., Ingram, A.J., 2001. Akt is activated in response to an apoptotic signal. J. Biol. Chem. 8, 8.
129. Tenzer, A., Zingg, D., Rocha, S., Hemmings, B., Fabbro, D., Glanzmann, C., Schubiger, P.A., Bodis, S., Pruschy, M., 2001. The phosphatidylinositide 3-kinase/Akt survival pathway is a target for the anticancer and radiosensitizing agent PKC412 an inhibitor of protein kinase C. Cancer Res. 61, 8203-8210.
130. Testa, J.R., Bellacosa, A., 2001. AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 98, 10983-10985.
131. Toker, A., 2000. Protein kinases as mediators of phosphoinositide 3-kinase signaling, Mol. Pharmacol. 57, 652-658.
132. Toker, A., Newton, A.C., 2000. Cellular signaling pivoting around PDK-1. Cell 103, 185-188.
133. Vanhaesebroeck, B., Waterfield, M.D., 1999. Signaling by distinct classes of phosphoinositide 3-quinces. Exp. Cell Res. 253, 239-254.
134. Vanhaesebroeck, B., Alessi, D.R., 2000. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J. 346, 561-576.
135. Varticovski, L., Lu, Z.R., Mitchell, K., de Aos, I., Kopecek, J., 2001. Water-soluble HPMA copolymer-wortmannin conjugate retains phosphoinositide 3-kinase inhibitory activity in vitro and in vivo. J. Control Release 74, 275-281.
136. Vivanco, I., Sawyers, C.L., 2002. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489-501.
137. Kip1 by PKB/Akt-mediated phosphorylation in breast cancer. Nat. Med. 8, 1136-1144.
138. Vlahos, C.J., Matter, W.F., Hui, K.Y., Brown, R.F., 1994. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one(LY294002). J. Biol. Chem. 269, 5241-5248.
139. Wan, X., Yokoyama, Y., Shinohara, A., Takahashi, Y., Tamaya, T., 2002. PTEN augments staurosporine-induced apoptosis in PTEN-null Ishikawa cells by downregulating PI3K/Akt signaling pathway. Cell Death Differ. 9, 414-420.
140. Wang, Q., Li, N., Wang, X., Kim, M.M., Evers, B.M., 2002. Augmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3′-kinase inhibition in the KM20 human colon cancer cell line. Clin. Cancer Res. 8, 1940-1947.
141. Xagorari, A., Papapetropoulos, A., Mauromatis, A., Economou, M., Fotsis, T., Roussos, C., 2001. Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages. J. Pharmacol. Exp. Ther. 296, 181-187.
142. Xia, W., Mullin, R.J., Keith, B.R., Liu, L.H., Ma, H., Rusnak, D.W., Owens, G., Alligood, K.J., Spector, N.L., 2002. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21, 6255-6263.
143. Yakes, F.M., Chinratanalab, W., Ritter, C.A., King, W., Seelig, S., Arteaga, C.L., 2002. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res. 62, 4132-4141.
144. Yoshizumi, M., Tsuchiya, K., Kirima, K., Kyaw, M., Suzaki, Y., Tamaki, T., 2001. Quercetin inhibits Shc- and phosphatidylinositol 3-kinase-mediated c-Jun N-terminal kinase activation by angiotensin II in cultured rat aortic smooth muscle cells. Mol. Pharmacol. 60, 656-665.
145. Yu, K., Toral-Barza, L., Discafani, C., Zhang, W.G., Skotnicki, J., Frost, P., Gibbons, J.J., 2001. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr. Related Cancer 8, 249-258.
146. Yuan, Z.Q., Sun, M., Feldman, R.I., Wang, G., Ma, X., Jiang, C., Coppola, D., Nicosia, S.V., Cheng, J.Q., 2000. Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Oncogene 19, 2324-2330.
147. Zha, J., Harada, H., Yang, E., Jockel, J., Korsmeyer, S.J., 1996. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-LL. Cell 87, 619-628.
148. Zhou, B.P., Liao, Y., Xia, W., Spohn, B., Lee, M.H., Hung, M.C., 2001. Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat. Cell Biol. 3, 245-252.