Abstract
Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase and generates phosphatidylinositol-3,4,5-trisphosphate (PI(3, 4, 5)P3). PI(3, 4, 5)P3 is a second messenger essential for the translocation of Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (PDK) 1 and PDK2. Activation of Akt plays a pivotal role in fundamental cellular functions such as cell proliferation and survival by phosphorylating a variety of substrates. In recent years, it has been reported that alterations to the PI3K-Akt signaling pathway are frequent in human cancer. Constitutive activation of the PI3K-Akt pathway occurs due to amplification of the PIK3C gene encoding PI3K or the Akt gene, or as a result of mutations in components of the pathway, for example PTEN (phosphatase and tensin homologue deleted on chromosome 10), which inhibit the activation of Akt. Several small molecules designed to specifically target PI3K-Akt have been developed, and induced cell cycle arrest or apoptosis in human cancer cells in vitro and in vivo. Moreover, the combination of an inhibitor with various cytotoxic agents enhances the anti-tumor efficacy. Therefore, specific inhibition of the activation of Akt may be a valid approach to treating human malignancies and overcoming the resistance of cancer cells to radiation or chemotherapy.
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Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three Akts. Genes Dev 1999; 13: 2905–2927.
Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489–501.
Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP. Impaired fas response and autoimmunity in Pten+/− mice. Science 1999; 285: 2122–2125.
Hill M, Hemmings B. Inhibition of protein kinase B/Akt. Implications for cancer therapy. Pharmacol Ther 2002; 93: 243.
Nicholson KM, Anderson NG. The protein kinase B/Akt signaling pathway in human malignancy. Cell Signal 2002; 14: 381–395.
Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA 2001; 98: 10983–10985.
Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem 1998; 67: 481–507.
Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: Implications for development, homeostasis, and cancer. Ann Rev Cell Dev Biol 2001; 17: 615–675.
Vanhaesebroeck B, Waterfield MD. Signaling by distinct classes of phosphoinositide 3-quinces. Exp Cell Res 1999; 253: 239–254.
Pawson T, Nash P. Protein-protein interaction define specificity in signal transduction. Gene Dev 2000; 14: 1027–1047.
Bottomley MJ, Salim K, Panayotou G. Phospholipid-binding protein domains. Biochem Biophys Acta 1998; 1436: 165–183.
Rameh LE, Cantley LC. The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem 1999; 274: 8347–8350.
Fruman DA, Rameh LE, Cantley LC. Phosphoinositide binding domains: Embracing 3-phosphate. Cell 1999; 97: 817–820.
Staal SP. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: Amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci USA 1987; 84: 5034–5037.
Jones PF, Jakubowicz T, Pitossi FJ, Maurer F, Hemmings BA. Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc Natl Acad Sci USA 1991; 88: 4171–4175.
Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem 1991; 201: 475–481.
Bellacosa A, Testa JR, Staal SP, Tsichlis PN. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 1991; 254: 274–277.
Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): A multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J 1998; 335: 1–13.
Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: More than just a road to PKB. Biochem J 2000; 346: 561–576.
Altomare DA, Guo K, Cheng JQ, Sonoda G, Walsh K, Testa JR. Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene. Oncogene 1995; 11: 1055–1060.
Altomare DA, Lyons GE, Mitsuuchi Y, Cheng JQ, Testa JR. Akt2 mRNA is highly expressed in embryonic brown fat and the Akt2 kinase is activated by insulin. Oncogene 1998; 16: 2407–2411.
Brodbeck D Cron P, Hemmings BA. A human protein kinase B with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. J Biol Chem 1999; 274: 9133–9136.
Staal SP, Huebner K, Croce CM, Parsa NZ, Testa JR. The AKT1 proto-oncogene maps to human chromosome 14, band q32. Genomics 1988; 2: 96–98.
Cheng JQ, Godwin AK, Bellacosa A, et al. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/ threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci USA 1992; 89: 9267–9271.
Nakatani K, Thompson DA, Barthel A, et al. Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer cell lines. J Biol Chem 1999; 274: 21528–21532.
Alessi DR, Andjelkovic M, Caudwell B, et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 1996; 15: 6541–6551.
Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411: 355–365.
Lynch DK, Ellis CA, Edwards PA, Hiles ID. Integrin-linked kinase regulates phosphorylation of serin 473 of protein kinase B by an indirect mechanism. Oncogene 1999; 18: 8024–8032.
Persad S, Attwell S, Gray V, et al. Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-limked kinase: Critical roles for kinase activity and amino acids arginine 211 and serine 343. J Biol Chem 2001; 276: 27462–27469.
Delcommenne M, Tan C, Gray V, et al. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 1998; 95: 11211–11216.
Meier R, Hemmings BA. Regulation of protein kinase B. J Recept Signal Transduct Res 1999; 19: 121–128.
Cross D, Alessi D, Cohen P, Andjelkovich M, Hemmings B. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378: 785–789.
Lawlor MA, Alessi DR. PKB/Akt: A key mediator of cell proliferation, survival and insulin responses? J Cell Sci 2001; 114: 2903–2910.
Wang Q, Somwar R, Bilan PJ, et al. Protein kinase /Akt participates in GLUT4 translocation by insulin in L6 myoblasts. Mol Cell Biol 1999; 19: 4008–4018.
Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998; 12: 3499–3511.
Liang J, Zubovitz J, Petrocelli T, et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 2002; 8: 1153–1160.
Medema RH, Kops GJ, Bos JL, Burgering BM. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 2000; 404: 782–787.
Shin I, Yakes FM, Rojo F, et al. PKB/Akt mediates cell cycle progression by phosphorylation of p27kip1 at threonine 157 and modulation of its cellular localization. Nat Med 2002; 8: 1145–1152.
Viglietto G, Motti ML, Bruni P, et al. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27kip1 by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 2002; 8: 1136–1144.
Zhou BP, Liao Y, Xia W, Sphon B, Lee MH, Hung MC. Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 2001; 3: 245–252.
Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. 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 1999; 344: 427–431.
Sekulic A, Hudson CC, Homme JL, et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling path-way and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 2000; 60: 3504–3513.
McManus EJ, Alessi DR. TSC1-TSC2: A complex tale of PKB-mediated S6K regulation. Nat Cell Biol 2002; 4: E214-E216.
Gao N, Flynn DC, Zhang Z, et al. The G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells. Am J Physiol Cell Physiol 2004 (in press).
Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrorm SE, Tsichlis PN, Rosen N. Cyclin D expression is con-trolled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 1998; 273: 29864–29872.
Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4: 648–657.
Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and-2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci USA 2002; 99: 13571–13576.
Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002; 4: 658–665.
Biondi RM, Kieloch A, Currie RA, Deak M, Alessi DR. The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J 2001; 20: 4380–4390.
Li Y, Corradetti MN, Inoki K, Guan KL. TSC2: Filling the GAP in the mTOR signaling pathway. Trends Biochem Sci 2004; 29: 32–38.
Yao R, Cooper GM. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 1995; 267: 2003–2006.
Franke TF, Kaplan DR, Cantley LC. PI3K: Downstream AK-Tion blocks apoptosis. Cell 1997; 88: 435–437.
Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 1998; 10: 262–267.
Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signaling pathway and cancer. Cancer Treat Rev 2004; 30: 193–204.
Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91: 231–241.
Del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997; 278: 687–689.
Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 1999; 401: 82–85.
Kane LP, Shapiro VS, Stokoe D, Weiss A. Induction of NF-κB by the Akt/PKB kinase. Curr Biol 1999; 9: 601–604.
Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-κB transcription factors. Oncogene 1999; 18: 6910–6924.
Lauder A, Castellanos A, Weston K. c-Myb transcription is activated by protein kinase B (PKB) following interleukin 2 stimulationof T cell and is required for PKB-mediated protein from apoptosis. Mol Cell biol 2001; 21: 5797–5805.
Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 1998; 273: 32377–32379.
Pugazhenthi S, Nesterova A, Sable C, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 2000; 275: 10761–10766.
Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF. The anti-apoptotic gene mcl-1 is up-regulated by the phosphadylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol 1999; 19: 6195–6206.
Osaki M, Kase S, Adachi K, Takeda A, Hashimoto K, Ito H. Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45. J Cancer Res Clin Oncol 2004; 130: 8–14.
Reusch JE, Klemm DJ. Inhibition of cAMP-response element-binding protein activity decreases protein kinase B/Akt expression in 3T3-L1 adipocytes and induces apoptosis. J Biol Chem 2002; 277: 1426–1432.
Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001; 411: 342–348.
Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 2001; 98: 11598–11603.
Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC. HER-2/ neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 2001b; 3: 973–982.
Myers MP, Tonks NK. PTEN: Sometimes taking it off can be better than putting it on. Am J Hum Genet 1997; 61: 1234–1238.
Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 1999; 96: 4240–4245.
Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273: 13375–13378.
Eng C. PTEN: One gene, many syndromes. Hum Mutat 2003; 22: 183–198.
Wu H, Goel V, Haluska FG. PTEN signaling pathway in melanoma. Oncogene 2003; 22: 3113–3122.
Munoz J, Lazcoz P, del Mar Inda M, et al. Homozygous deletion and expression of PTEN and DMBT1 in human primary neuroblastoma and cell lines. Int J Cancer 2004; 109: 673–679.
Karoui M, Tresallet C, Julie C, et al. Loss of heterozygosity on 10q and mutational status of PTEN and BMPR1A in colorectal primary tumours and metastases. Br J Cancer 2004; 90: 1230–1234.
Nassif NT, Lobo GP, Wu X, et al. PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene 2004; 23: 617–628.
Simpson L, Parsons R. PTEN: Life as a tumor suppressor. Exp Cell Res 2001; 264: 29–41.
Taylor V, Wong M, Brandts C, et al. 5' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells. Mol Cell Biol 2000; 20: 6860–6871.
Leslie Nr, Biondi RM, Alessi DR. Phosphoinositide-regulated kinases and phosphoinositide phosphatases. Chem Rev 2001; 101: 2365–2380.
Maira SM, Galetic I, Brazil DP, et al. Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science 2001; 294: 374–380.
Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: Receptor heterodimerization in development and cancer. EMBO J 2000; 19: 3159–3167.
Siegel PM, Ryan ED, Cardiff RD, Muller WJ. Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: Implications for human breast cancer. EMBO J 1999; 18: 2149–2164.
Zhou BP, Hu MC, Miller SA, et al. HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway. J Biol Chem 2000; 275: 8027–7031.
Prigent SA, Gullick WJ. Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J 1994; 13: 2831–2841.
Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304: 554.
Shayasteh L, Lu Y, Kuo WL, et al. PI3CA is implicated as an oncogene in ovarian cancer. Nat Genet 1999; 21: 99–102.
Ma YY, Wei SJ, Lin YC, et al. PIK3CA as an oncogene in cervical cancer. Oncogene 2000; 19: 2739–2744.
Woenckhaus J, Steger K, Werner E, et al. Genomic gain of PIK3CA and increased expression of p110alpha are associated with progression of dysplasia into invasive squamous cell carcinoma. J Pathol 2002; 198: 335–342.
Byun DS, Cho K, Ryu BK, et al. Frequent monoallelic deletion of PTEN and its reciprocal association with PIK3CA amplification in gastric carcinoma. Int J Cancer 2003; 104: 318–327.
Knobbe CB, Reifenberger G. Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol 2003; 13: 507–518.
Bellacosa A, de Feo D, Godwin AK, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 1995; 64: 280–285.
Cheng JQ, Ruggeri B, Klein WM, et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 1996; 93: 3636–3641.
Frisk T, Foukakis T, Dwight T, et al. Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer. Genes Chromosomes Cancer 2002; 35: 74–80.
Garcia JM, Silva JM, Dominguez G, et al. Allelic loss of the PTEN region (10q23) in breast carcinomas of poor pathophenotype. Breast Cancer Res Treat 1999; 57: 237–243.
Wang DS, Rieger-Christ K, Latini JM, et al. Molecular analysis of PTEN and MXI1 in primary bladder carcinoma. Int J Cancer 2000; 88: 620–625.
Ittmann MM. Chromosome 10 alterations in prostate adeno-carcinoma Oncol Rep 1998; 5: 1329–1335.
An HJ, Logani S, Isacson C, Ellenson LH. Molecular characterization of uterine clear cell carcinoma. Mod Pathol 2004; 17: 530–537.
Rasheed BK, Wiltshire RN, Bigner SH, Bigner DD. Molecular pathogenesis of malignant gliomas. Curr Opin Oncol 1999; 11: 162–167.
Saito T, Oda Y, Kawaguchi K, et al. PTEN and other tumor suppressor gene mutations as secondary genetic alterations in synovial sarcoma. Oncol Rep 2004; 11: 1011–1015.
Goel A, Arnold CN, Niedzwiecki D, et al. Frequent inactivation of PTENby promoter hypermathylation in microsatellite instablity-high sporadic colorectal cancers. Cancer Res 2004; 64: 3014–3021.
Kandel ES, Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res 1999; 253: 210–229.
Roy HK, Olusola BF, Clemens DL, et al. AKT proto-oncogene overexpression is an early event during sporadic colon carcino-genesis. Carcinogenesis 2002; 23: 201–205.
Altomare DA, Tanno S, DeRienzo A, et al. Frequent activation of AKT2 kinase in human pancreatic carcinomas. J Cell Biochem 2003; 88: 470–476.
Tanno S, Yanagawa N, Habiro A, et al. Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance. Cancer Res 2004; 64: 3486–3490.
Alkan S, Izban KF. Immunohistochemical localization of phosphorylated AKTin multiple myeloma. Blood 2002; 99: 2278–2279.
Gupta AK, McKenna WG, Weber CN, et al. Local recurrence in head and neck cancer: Relationship to radiation resistance and signal transduction. Clin Cancer Res 2002; 8: 885–892.
Hsu J, Shi Y, Krajewski S, et al. The AKTkinase is activated in multiple myeloma tumor cells. Blood 2001; 98: 2853–2855.
Kanamori Y, Kigawa J, Itamochi H, et al. Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma. Clin Cancer Res 2001; 7: 892–895.
Kurose K, Zhou XP, Araki T, Cannistra SA, Maher ER, Eng C. 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 2001; 158: 2097–2106.
Malik SN, Brattain M, Ghosh PM, et al. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res 2002; 8: 1168–1171.
Nakayama H, Ikebe T, Beppu M, Shirasuna K. High expression levels of nuclear factor kappaB, IkappaB kinase alpha and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer 2001; 92: 3037–3044.
Semba S, Moriya T, Kimura W, Yamakawa M. Phosphorylated Akt/PKB controls cell growth and apoptosis in intraductal papillary-mucinous tumor and invasive ductal adeno-carcinoma of the pancreas. Pancreas 2003; 26: 250–257.
Sun M, Wang G, Paciga JE, et al. AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol 2001; 159: 431–437.
Yuan ZQ, Sun M, Feldman RI, et al. Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Oncogene 2000; 19: 2324–2330.
Yamamoto S, Tomita Y, Hoshida Y, et al. Prognostic significance of activated Akt expression in pancreatic ductal adeno-carcinoma. Clin Cancer Res 2004; 10: 2846–2850.
Nam SY, Lee HS, Jung GA, et al. Akt/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis. APMIS 2003; 111: 1105–1113.
Perez-Tenorio G, Stal O. Activation of AKT/PKB in breast cancer predicts a worse outcoming among endocrine treated patients. Br J Cancer 2002; 86: 540–545.
Lee JI, Soria JC, Hassan KA, et al. Loss of PTEN expression as a prognostic marker for tongue cancer. Arch Otolaryngol Head Neck Surg 2001; 127; 1441–1445.
Ermoian RP, Furniss CS, Lamborn KR, et al. Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. Clin Cancer Res 2002; 8: 1100–1106.
Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 2002; 1: 707–717.
Brognard J, Clark AS, Ni Y, Dennis PA. Akt/protein kinase b isconstitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 2001; 61: 3986–3997.
Powis G, Bonjouklian R, Berggren MM, et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 1994; 54: 2419–2433.
Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000; 351: 95–105.
Schultz RM, Merriman RL, Andis SL, et al. In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res 1995; 15: 1135–1139.
Lemke LE, Paine-Murrieta GD, Taylor CW, Powis G. Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensive phosphatidylinositol-3-kinase. Cancer Chenother Pharmacol 1999; 44: 491–497.
Ng SS, Tsao MS, Chow S, Hedley DW. Inhibition of phos-phatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res 2000; 60: 5451–5455.
Varticovski L, Lu ZR, Mitchell K, de Aos I, Kopecek J. Water-solble HPMAcopolymer-wortmannin conjugate retains phos-phoinositide 3-kinase inhibitory activety in vitro and in vivo. J Control Release 2001; 74: 275–281.
Sanchez-Margalet V, Goldfine ID, Vlahos CJ, Sung CK. Role of phosphatidylinositol-3-kinase in insulin receptor signaling: Studies with inhibitor, LY294002. Biochem Biophys Res Commun 1994; 204: 446–452.
Takeda A, Osaki M, Adachi K, Honjo S, Ito H. Role of the phosphatidylinositol 3'-kinase-Akt signal pathway in the proliferation of human pancreatic ductal carcinoma cell lines. Pancreas 2004; 28: 353–358.
Semba S, Itoh N, Ito M, Harada M, Yamakawa M. 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 2002; 8: 1957–1963.
Itoh N, Semba S, Ito M, Takeda H, Kawata S, Yamakawa M. Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer 2002; 94: 3127–3134.
Hu L, Zaloudek C, Mills GB, Gray J, Jaffe RB. In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin Cancer Res 2000; 6: 880–886.
Hu L, Hofmann J, Lu Y, Mills GB, Jaffe RB. Inhibition of phosphatidylinositol 3'-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res 2002; 62: 1087–1092.
Rosenzweig KE, Youmell MB, Palayoor ST, Price BD. Radiosensitization of human tumor cells by the phosphatidylinositol-3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. Clin Cancer Res 1997; 3: 1149–1156.
Sarkaria JN, Tibbetts RS, Busby EC, et al. Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res 1998; 58: 4375–4382.
Kim SH, Um JH, Dong-Won B, et al. Potensiation of chemosensitivity in multidrug-resistant human leukemia CEM cells by inhibition of DNA-dependent protein kinase using wotmannin. Leuk Res 2000; 24: 917–925.
Wang Q, Li N, Wang X, Kim MM, Evers BM. Augmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3'-kinase inhibition in the KM20 human colon cancer cell line. Clin Cancer Res 2002; 8: 1940–1947.
Edwards E, Geng L, Tan J, Onishko H, Donnelly E, Hallahan DE. Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Res 2002; 62: 4671–4677.
Asselin E, Mills GB, Tsang BK. XIAP regulates Akt activety and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epthelial cancer cells. Cancer Res 2001; 61: 1862–1868.
Klejman A, Rushen L, Morrione A, Slupianek A, Skorski T. Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. Oncogene 2002; 21: 5868–5876.
Castillo SS, Brognard J, Petukhov PA, et al. Preferential inhibition of Akt and killing of Akt-dependent cancer cells by rationally designed phosphatidylinositol ether lipid analogues. Cancer Res 2004; 64: 2782–2792.
Nakanishi K, Sakamoto M, Yasuda J, et al. Critical involvement of the phosphatidylinositol 3-kinase/Akt pathway in anchorage-independent growth and hematogenous intrahepatic metastasis of liver cancer. Cancer Res 2002; 62: 2971–2975.
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Osaki, M., Oshimura, M. & Ito, H. PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis 9, 667–676 (2004). https://doi.org/10.1023/B:APPT.0000045801.15585.dd
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DOI: https://doi.org/10.1023/B:APPT.0000045801.15585.dd