Several growth-promoting signaling pathways have tight molecular connections with metabolic-related signal transduction systems. By controlling these pathways, cancer cells gain autonomy over energy-acquiring systems and, thus, expand their potential for proliferation. Here, we discuss the use of drug and antisense oligonucleotide approaches to inhibit metabolic pathways in cancer cells and their potential use in the therapeutics of cancer. © 2006 Bentham Science Publishers Ltd.617787Gough, N.R., Ray, L.B., Mapping cellular signaling (2002) Sci. STKE, pp. EG8Levchenko, A., Computational cell biology in the post-genomic era (2001) Mol. Biol. Rep., 28, pp. 83-89Venter, J.C., Adams, M.D., Myers, E.W., Li, P.W., Mural, R.J., Sutton, G.G., Smith, H.O., Yan, C., The sequence of the human genome (2001) Science, 291, pp. 1304-1351Kolch, W., Calder, M., Gilbert, D., When kinases meet mathematics, the systems biology of MAPK signalling (2005) FEBS Lett., 579, pp. 1891-1895Whitman, M., Downes, C.P., Keeler, M., Keller, T., Cantley, L., Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate (1988) Nature, 332, pp. 644-646Talmage, D.A., Freund, R., Young, A.T., Dahl, J., Dawe, C.J., Benjamin, T.L., Phosphorylation of middle T by pp60c-src, a switch for binding of phosphatidylinositol 3-kinase and optimal tumorigenesis (1989) Cell, 59, pp. 55-65Jones, P.F., Jakubowicz, T., Pitossi, F.J., Maurer, F., Hemmings, B.A., Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily (1991) Proc. Natl. Acad. Sci. USA, 88, pp. 4171-4175Franke, T.F., Yang, S.I., Chan, T.O., Datta, K., Kazlauskas, A., Morrison, D.K., Kaplan, D.R., Tsichlis, P.N., The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase (1995) Cell, 81, pp. 727-736Fruman, D.A., Meyers, R.E., Cantley, L.C., Phosphoinositide kinases (1998) Ann. Rev. Biochem., 67, pp. 481-507Cantley, L.C., The phosphoinositide 3-kinase pathway (2002) Science, 296, pp. 1655-1657Klarlund, J.K., Guilherme, A., Holik, J.J., Virbasius, J.V., Chawla, A., Czech, M.P., Signaling by phosphoinositide-3,4,5-trisphosphate through proteins containing pleckstrin and Sec7 homology domains (1997) Science, 275, pp. 1927-1930Scharenberg, A.M., El-Hillal, O., Fruman, D.A., Beitz, L.O., Li, Z., Lin, S., Gout, I., Kinet, J.P., Phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3)/Tec kinase-dependent calcium signaling pathway, a target for SHIP-mediated inhibitory signals (1998) EMBO J., 17, pp. 1961-1972Tanti, J.F., Grillo, S., Gremeaux, T., Coffer, P.J., Van Obberghen, E., Le Marchand-Brustel, Y., Potential role of protein kinase B in glucose transporter 4 translocation in adipocytes (1997) Endocrinology, 138, pp. 2005-2010Dudek, H., Datta, S.R., Franke, T.F., Birnbaum, M.J., Yao, R., Cooper, G.M., Segal, R.A., Greenberg, M.E., Regulation of neuronal survival by the serine-threonine protein kinase Akt (1997) Science, 275, pp. 661-665Kohn, A.D., Summers, S.A., Birnbaum, M.J., Roth, R.A., Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation (1996) J. Biol. Chem., 271, pp. 31372-31378Bellacosa, A., Testa, J.R., Staal, S.P., Tsichlis, P.N., A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region (1991) Science, 254, pp. 274-277Cheng, J.Q., Godwin, A.K., Bellacosa, A., Taguchi, T., Franke, T.F., Hamilton, T.C., Tsichlis, P.N., Testa, J.R., AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/ threonine kinases, is amplified in human ovarian carcinomas (1992) Proc. Natl. Acad. Sci. USA, 89, pp. 9267-9271Brodbeck, D., Cron, P., Hemmings, B.A., A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain (1999) J. Biol. Chem., 274, pp. 9133-9136Stephens, L., Anderson, K., Stokoe, D., Erdjument-Bromage, H., Painter, G.F., Holmes, A.B., Gaffney, P.R., Hawkins, P.T., Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B (1998) Science, 279, pp. 710-714Delcommenne, M., Tan, C., Gray, V., Rue, L., Woodgett, J., Dedhar, S., Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase (1998) Proc. Natl. Acad. Sci. USA, 95, pp. 11211-11216Alessi, D.R., Andjelkovic, M., Caudwell, B., Cron, P., Morrice, N., Cohen, P., Hemmings, B.A., Mechanism of activation of protein kinase B by insulin and IGF-1 (1996) EMBO J., 15, pp. 6541-6551Williams, M.R., Arthur, J.S., Balendran, A., Van Der Kaay, J., Poli, V., Cohen, P., Alessi, D.R., The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells (2000) Curr. Biol., 10, pp. 439-448Feng, J., Park, J., Cron, P., Hess, D., Hemmings, B.A., Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase (2004) J. Biol. Chem., 279, pp. 41189-41196Sarbassov, D.D., Guertin, D.A., Ali, S.M., Sabatini, D.M., Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex (2005) Science, 307, pp. 1098-1101Hanada, M., Feng, J., Hemmings, B.A., Structure, regulation and function of PKB/AKT - A major therapeutic target (2004) Biochim. Biophys. Acta, 1697, pp. 3-16Alessi, D.R., Caudwell, F.B., Andjelkovic, M., Hemmings, B.A., Cohen, P., Molecular basis for the substrate specificity of protein kinase Bcomparison with MAPKAP kinase-1 and p70 S6 kinase (1996) FEBS Lett., 399, pp. 333-338Obata, T., Yaffe, M.B., Leparc, G.G., Piro, E.T., Maegawa, H., Kashiwagi, A., Kikkawa, R., Cantley, L.C., Peptide and protein library screening defines optimal substrate motifs for AKT/PKB (2000) J. Biol. Chem., 275, pp. 36108-36115Staal, S.P., Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2, amplification of AKT1 in a primary human gastric adenocarcinoma (1987) Proc. Natl. Acad. Sci. USA, 84, pp. 5034-5037Del Peso, L., Gonzalez-Garcia, M., Page, C., Herrera, R., Nunez, G., Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt (1997) Science, 278, pp. 687-689Datta, S.R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., Greenberg, M.E., Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery (1997) Cell, 91, pp. 231-241Downward, J., How BAD phosphorylation is good for survival (1999) Nat. Cell Biol., 1, pp. E33-E35Cardone, M.H., Roy, N., Stennicke, H.R., Salvesen, G.S., Franke, T.F., Stanbridge, E., Frisch, S., Reed, J.C., Regulation of cell death protease caspase-9 by phosphorylation (1998) Science, 282, pp. 1318-1321Trencia, A., Perfetti, A., Cassese, A., Vigliotta, G., Miele, C., Oriente, F., Santopietro, S., Beguinot, F., Protein kinase B/Akt binds and phosphorylates PED/PEA-15, stabilizing its antiapoptotic action (2003) Mol. Cell. Biol., 23, pp. 4511-4521Kim, A.H., Khursigara, G., Sun, X., Franke, T.F., Chao, M.V., Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 (2001) Mol. Cell. Biol., 21, pp. 893-901Barthwal, M.K., Sathyanarayana, P., Kundu, C.N., Rana, B., Pradeep, A., Sharma, C., Woodgett, J.R., Rana, A., Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival (2003) J. Biol. Chem., 278, pp. 3897-3902Rena, G., Guo, S., Cichy, S.C., Unterman, T.G., Cohen, P., Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B (1999) J. Biol. Chem., 274, pp. 17179-17183Biggs III, W.H., Meisenhelder, J., Hunter, T., Cavenee, W.K., Arden, K.C., Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1 (1999) Proc. Natl. Acad. Sci. USA, 96, pp. 7421-7426Wolfrum, C., Besser, D., Luca, E., Stoffel, M., Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization (2003) Proc. Natl. Acad. Sci. USA, 100, pp. 11624-11629Burgering, B.M., Medema, R.H., Decisions on life and death, FOXO Forkhead transcription factors are in command when PKB/Akt is off duty (2003) J. Leukoc. Biol., 73, pp. 689-701Jones, R.G., Parsons, M., Bonnard, M., Chan, V.S., Yeh, W.C., Woodgett, J.R., Ohashi, P.S., Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and Bcl-X(L) levels in vivo (2000) J. Exp. Med., 191, pp. 1721-1734Du, K., Montminy, M., CREB is a regulatory target for the protein kinase Akt/PKB (1998) J. Biol. Chem., 273, pp. 32377-32379Pekarsky, Y., Hallas, C., Palamarchuk, A., Koval, A., Bullrich, F., Hirata, Y., Bichi, R., Croce, C.M., Akt phosphorylates and regulates the orphan nuclear receptor Nur77 (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 3690-3694Lin, H.K., Yeh, S., Kang, H.Y., Chang, C., Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 7200-7205Basu, S., Totty, N.F., Irwin, M.S., Sudol, M., Downward, J., Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis (2003) Mol. Cell, 11, pp. 11-23Zhou, B.P., Liao, Y., Xia, W., Spohn, B., Lee, M.H., Hung, M.C., Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells (2001) Nat. Cell Biol., 3, pp. 245-252Li, Y., Dowbenko, D., Lasky, L.A., AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival (2002) J. Biol. Chem., 277, pp. 11352-11361Viglietto, G., Motti, M.L., Bruni, P., Melillo, R.M., D'Alessio, A., Califano, D., Vinci, F., Santoro, M., Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer (2002) Nat. Med., 8, pp. 1136-1144Shin, I., Yakes, F.M., Rojo, F., Shin, N.Y., Bakin, A.V., Baselga, J., Arteaga, C.L., PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization (2002) Nat. Med., 8, pp. 1145-1152Mayo, L.D., Donner, D.B., A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 11598-11603Okumura, E., Fukuhara, T., Yoshida, H., Hanada Si, S., Kozutsumi, R., Mori, M., Tachibana, K., Kishimoto, T., Akt inhibits Myt1 in the signalling pathway that leads to meiotic G2/M-phase transition (2002) Nat. Cell Biol., 4, pp. 111-116Zhang, R., Wang, H., Agrawal, S., Novel antisense anti-MDM2 mixed-backbone oligonucleotides, proof of principle, in vitro and in vivo activities, and mechanisms (2005) Curr. Cancer Drug Targets, 5, pp. 43-49Buolamwini, J.K., Addo, J., Kamath, S., Patil, S., Mason, D., Ores, M., Small molecule antagonists of the MDM2 oncoprotein as anticancer agents (2005) Curr. Cancer Drug Targets, 5, pp. 57-68Saltiel, A.R., Kahn, C.R., Insulin signalling and the regulation of glucose and lipid metabolism (2001) Nature, 414, pp. 799-806White, M.F., IRS proteins and the common path to diabetes (2002) Am. J. Physiol. Endocrinol. Metab., 283, pp. E413-E422Mauvais-Jarvis, F., Kahn, C.R., Understanding the pathogenesis and treatment of insulin resistance and type 2 diabetes mellitus, what can we learn from transgenic and knockout mice? (2000) Diabetes Metab., 26, pp. 433-448Araki, E., Lipes, M.A., Patti, M.E., Bruning, J.C., Haag III, B., Johnson, R.S., Kahn, C.R., Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene (1994) Nature, 372, pp. 186-190Withers, D.J., Burks, D.J., Towery, H.H., Altamuro, S.L., Flint, C.L., White, M.F., Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling (1999) Nat. Genet., 23, pp. 32-40Kido, Y., Burks, D.J., Withers, D., Bruning, J.C., Kahn, C.R., White, M.F., Accili, D., Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2 (2000) J. Clin. Invest., 105, pp. 199-205Araujo, E.P., De Souza, C.T., Gasparetti, A.L., Ueno, M., Boschero, A.C., Saad, M.J., Velloso, L.A., Short-term in vivo inhibition of insulin receptor substrate-1 expression leads to insulin resistance, hyperinsulinemia, and increased adiposity (2005) Endocrinology, 146, pp. 1428-1437Wang, L.M., Myers Jr., M.G., Sun, X.J., Aaronson, S.A., White, M., Pierce, J.H., IRS-1, essential for insulin- and IL-4-stimulated mitogenesis in hematopoietic cells (1993) Science, 261, pp. 1591-1594Taouis, M., Dupont, J., Gillet, A., Derouet, M., Simon, J., Insulin receptor substrate 1 antisense expression in an hepatoma cell line reduces cell proliferation and induces overexpression of the Src homology 2 domain and collagen protein (SHC) (1998) Mol. Cell Endocrinol., 137, pp. 177-186Waters, S.B., Yamauchi, K., Pessin, J.E., Functional expression of insulin receptor substrate-1 is required for insulin-stimulated mitogenic signaling (1993) J. Biol. Chem., 268, pp. 22231-22234Rose, D.W., Saltiel, A.R., Majumdar, M., Decker, S.J., Olefsky, J.M., Insulin receptor substrate 1 is required for insulin-mediated mitogenic signal transduction (1994) Proc. Natl. Acad. Sci. USA, 91, pp. 797-801Tanaka, S., Ito, T., Wands, J.R., Neoplastic transformation induced by insulin receptor substrate-1 overexpression requires an interaction with both Grb2 and Syp signaling molecules (1996) J. Biol. Chem., 271, pp. 14610-14616Ito, T., Sasaki, Y., Wands, J.R., Overexpression of human insulin receptor substrate 1 induces cellular transformation with activation of mitogen-activated protein kinases (1996) Mol. Cell Biol., 16, pp. 943-951D'Ambrosio, C., Keller, S.R., Morrione, A., Lienhard, G.E., Baserga, R., Surmacz, E., Transforming potential of the insulin receptor substrate 1 (1995) Cell Growth Differ., 6, pp. 557-562Fei, Z.L., D'Ambrosio, C., Li, S., Surmacz, E., Baserga, R., Association of insulin receptor substrate 1 with simian virus 40 large T antigen (1995) Mol. Cell Biol., 15, pp. 4232-4239Valentinis, B., Romano, G., Peruzzi, F., Morrione, A., Prisco, M., Soddu, S., Cristofanelli, B., Baserga, R., Growth and differentiation signals by the insulin-like growth factor 1 receptor in hemopoietic cells are mediated through different pathways (1999) J. Biol. Chem., 274, pp. 12423-12430Reiss, K., Wang, J.Y., Romano, G., Furnari, F.B., Cavenee, W.K., Morrione, A., Tu, X., Baserga, R., IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation (2000) Oncogene, 19, pp. 2687-2694Chang, Q., Li, Y., White, M.F., Fletcher, J.A., Xiao, S., Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors, therapeutic implications (2002) Cancer Res., 62, pp. 6035-6038Hoang, C.D., Zhang, X., Scott, P.D., Guillaume, T.J., Maddaus, M.A., Yee, D., Kratzke, R.A., Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells, association with distinct malignant phenotypes (2004) Cancer Res., 64, pp. 7479-7485Koda, M., Sulkowska, M., Kanczuga-Koda, L., Sulkowski, S., Expression of insulin receptor substrate 1 in primary breast cancer and lymph node metastases (2005) J. Clin. Pathol., 58, pp. 645-649Miranda, C., Greco, A., Miele, C., Pierotti, M.A., Van Obberghen, E., IRS-1 and IRS-2 are recruited by TrkA receptor and oncogenic TRK-T1 (2001) J. Cell Physiol., 186, pp. 35-46Traina, F., Carvalheira, J.B., Saad, M.J., Costa, F.F., Saad, S.T., BCR-ABL binds to IRS-1 and IRS-1 phosphorylation is inhibited by imatinib in K562 cells (2003) FEBS Lett., 535, pp. 17-22Jackson, J.G., White, M.F., Yee, D., Insulin receptor substrate-1 is the predominant signaling molecule activated by insulin-like growth factor-I, insulin, and interleukin-4 in estrogen receptor-positive human breast cancer cells (1998) J. Biol. Chem., 273, pp. 9994-10003Neid, M., Datta, K., Stephan, S., Khanna, I., Pal, S., Shaw, L., White, M., Mukhopadhyay, D., Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells (2004) J. Biol. Chem., 279, pp. 3941-3948Manning, B.D., Cantley, L.C., United at last, the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling (2003) Biochem. Soc. Trans., 31, pp. 573-578Bohni, R., Riesgo-Escovar, J., Oldham, S., Brogiolo, W., Stocker, H., Andruss, B.F., Beckingham, K., Hafen, E., Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4 (1999) Cell, 97, pp. 865-875Verdu, J., Buratovich, M.A., Wilder, E.L., Birnbaum, M.J., Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB (1999) Nat. Cell Biol., 1, pp. 500-506Scanga, S.E., Ruel, L., Binari, R.C., Snow, B., Stambolic, V., Bouchard, D., Peters, M., Manoukian, A.S., The conserved PI3′K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila (2000) Oncogene, 19, pp. 3971-3977Backman, S.A., Stambolic, V., Suzuki, A., Haight, J., Elia, A., Pretorius, J., Tsao, M.S., Mak, T.W., Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease (2001) Nat. Genet., 29, pp. 396-403Kwon, C.H., Zhu, X., Zhang, J., Knoop, L.L., Tharp, R., Smeyne, R.J., Eberhart, C.G., Baker, S.J., Pten regulates neuronal soma size, a mouse model of Lhermitte-Duclos disease (2001) Nat. Genet., 29, pp. 404-411Padberg, G.W., Schot, J.D., Vielvoye, G.J., Bots, G.T., De Beer, F.C., Lhermitte-Duclos disease and Cowden disease, a single phakomatosis (1991) Ann. Neurol., 29, pp. 517-523Potter, C.J., Huang, H., Xu, T., Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size (2001) Cell, 105, pp. 357-368Gomez, M.R., Phenotypes of the tuberous sclerosis complex with a revision of diagnostic criteria (1991) Ann. NY Acad. Sci., 615, pp. 1-7Young, J.M., Burley, M.W., Jeremiah, S.J., Jeganathan, D., Ekong, R., Osborne, J.P., Povey, S., A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients (1998) Ann. Hum. Genet., 62 (3 PART), pp. 203-213Montagne, J., Radimerski, T., Thomas, G., Insulin signaling, lessons from the Drosophila tuberous sclerosis complex, a tumor suppressor (2001) Sci. STKE, pp. PE36Dan, H.C., Sun, M., Yang, L., Feldman, R.I., Sui, X.M., Ou, C.C., Nellist, M., Cheng, J.Q., Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin (2002) J. Biol. Chem., 277, pp. 35364-35370Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J., Cantley, L.C., Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway (2002) Mol. Cell, 10, pp. 151-162Mills, G.B., Lu, Y., Kohn, E.C., Linking molecular therapeutics to molecular diagnostics, inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 10031-10033Carvalheira, J.B., Ribeiro, E.B., Araujo, E.P., Guimaraes, R.B., Telles, M.M., Torsoni, M., Gontijo, J.A., Saad, M.J., Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats (2003) Diabetologia, 46, pp. 1629-1640Schultz, R.M., Merriman, R.L., Andis, S.L., Bonjouklian, R., Grindey, G.B., Rutherford, P.G., Gallegos, A., Powis, G., In vitro and in vivo antitumor activity of the phosphatidylinositol-3- kinase inhibitor, wortmannin (1995) Anticancer Res., 15, pp. 1135-1139Hu, L., Zaloudek, C., Mills, G.B., Gray, J., Jaffe, R.B., In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002) (2000) Clin. Cancer Res., 6, pp. 880-886Stiles, B., Gilman, V., Khanzenzon, N., Lesche, R., Li, A., Qiao, R., Liu, X., Wu, H., Essential role of AKT-1/protein kinase B alpha in PTEN-controlled tumorigenesis (2002) Mol. Cell Biol., 22, pp. 3842-3851Nakamura, N., Ramaswamy, S., Vazquez, F., Signoretti, S., Loda, M., Sellers, W.R., Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN (2000) Mol. Cell Biol., 20, pp. 8969-8982Vezina, C., Kudelski, A., Sehgal, S.N., Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle (1975) J. Antibiot. (Tokyo), 28, pp. 721-726Podsypanina, K., Lee, R.T., Politis, C., Hennessy, I., Crane, A., Puc, J., Neshat, M., Parsons, R., An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in PTEN+/- mice (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 10320-10325Neshat, M.S., Mellinghoff, I.K., Tran, C., Stiles, B., Thomas, G., Petersen, R., Frost, P., Sawyers, C.L., Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 10314-10319Aoki, M., Blazek, E., Vogt, P.K., A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 136-141Opalinska, J.B., Gewirtz, A.M., Therapeutic potential of antisense nucleic acid molecules (2003) Sci. STKE, pp. PE47Opalinska, J.B., Gewirtz, A.M., Nucleic-acid therapeutics, basic principles and recent applications (2002) Nat. Rev. Drug Discov., 1, pp. 503-514Crooke, S.T., Molecular mechanisms of action of antisense drugs (1999) Biochim. Biophys. Acta, 1489, pp. 31-44Lima, W.F., Wu, H., Crooke, S.T., Human RNases H (2001) Methods Enzymol., 341, pp. 430-440Reed, J.C., Double identity for proteins of the Bcl-2 family (1997) Nature, 387, pp. 773-776Pirollo, K.F., Rait, A., Sleer, L.S., Chang, E.H., Antisense therapeutics, from theory to clinical practice (2003) Pharmacol. Ther., 99, pp. 55-77Waters, J.S., Webb, A., Cunningham, D., Clarke, P.A., Raynaud, F., Di Stefano, F., Cotter, F.E., Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma (2000) J. Clin. Oncol., 18, pp. 1812-1823Webb, A., Cunningham, D., Cotter, F., Clarke, P.A., Di Stefano, F., Ross, P., Corbo, M., Dziewanowska, Z., BCL-2 antisense therapy in patients with non-Hodgkin lymphoma (1997) Lancet, 349, pp. 1137-1141Michael, D., Oren, M., The p53 and Mdm2 families in cancer (2002) Curr. Opin. Genet. Dev., 12, pp. 53-59Chen, L., Lu, W., Agrawal, S., Zhou, W., Zhang, R., Chen, J., Ubiquitous induction of p53 in tumor cells by antisense inhibition of MDM2 expression (1999) Mol. Med., 5, pp. 21-34Tortora, G., Caputo, R., Damiano, V., Bianco, R., Chen, J., Agrawal, S., Bianco, A.R., Ciardiello, F., A novel MDM2 antisense oligonucleotide has anti-tumor activity and potentiates cytotoxic drugs acting by different mechanisms in human colon cancer (2000) Int. J. Cancer, 88, pp. 804-809Wang, H., Nan, L., Yu, D., Agrawal, S., Zhang, R., Antisense anti-MDM2 oligonucleotides as a novel therapeutic approach to human breast cancer, in vitro and in vivo activities and mechanisms (2001) Clin. Cancer Res., 7, pp. 3613-3624Bianco, R., Ciardiello, F., Tortora, G., Chemosensitization by antisense oligonucleotides targeting MDM2 (2005) Curr. Cancer Drug Targets, 5, pp. 51-56Lahn, M., Kohler, G., Sundell, K., Su, C., Li, S., Paterson, B.M., Bumol, T.F., Protein kinase C alpha expression in breast and ovarian cancer (2004) Oncology, 67, pp. 1-10Sliva, D., Signaling pathways responsible for cancer cell invasion as targets for cancer therapy (2004) Curr. Cancer Drug Targets, 4, pp. 327-336Denham, D.W., Franz, M.G., Denham, W., Zervos, E.E., Gower Jr., W.R., Rosemurgy, A.S., Norman, J., Directed antisense therapy confirms the role of protein kinase C-alpha in the tumorigenicity of pancreatic cancer (1998) Surgery, 124, pp. 218-223Nemunaitis, J., Holmlund, J.T., Kraynak, M., Richards, D., Bruce, J., Ognoskie, N., Kwoh, T.J., Eckhardt, S.G., Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer (1999) J. Clin. Oncol., 17, pp. 3586-3595Green, D.W., Roh, H., Pippin, J., Drebin, J.A., Antisense oligonucleotides, an evolving technology for the modulation of gene expression in human disease (2000) J. Am. Coll. Surg., 191, pp. 93-105Shields, J.M., Pruitt, K., McFall, A., Shaub, A., Der, C.J., Understanding Ras, 'it ain't over 'til it's over' (2000) Trends Cell Biol., 10, pp. 147-154Cunningham, C.C., Holmlund, J.T., Schiller, J.H., Geary, R.S., Kwoh, T.J., Dorr, A., Nemunaitis, J., A phase I trial of c-Raf kinase antisense oligonucleotide ISIS 5132 administered as a continuous intravenous infusion in patients with advanced cancer (2000) Clin. Cancer Res., 6, pp. 1626-1631Stevenson, J.P., Yao, K.S., Gallagher, M., Friedland, D., Mitchell, E.P., Cassella, A., Monia, B., O'Dwyer, P.J., Phase I clinical/pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A) (1999) J. Clin. Oncol., 17, pp. 2227-2236Flaherty, K.T., Stevenson, J.P., O'Dwyer, P.J., Antisense therapeutics, lessons from early clinical trials (2001) Curr. Opin. Oncol., 13, pp. 499-505Velloso, L.A., Carneiro, E.M., Crepaldi, S.C., Boschero, A.C., Saad, M.J., Glucose- and insulin-induced phosphorylation of the insulin receptor and its primary substrates IRS-1 and IRS-2 in rat pancreatic islets (1995) FEBS Lett., 377, pp. 353-357Bruning, J.C., Winnay, J., Bonner-Weir, S., Taylor, S.I., Accili, D., Kahn, C.R., Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles (1997) Cell, 88, pp. 561-572Kulkarni, R.N., Bruning, J.C., Winnay, J.N., Postic, C., Magnuson, M.A., Kahn, C.R., Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes (1999) Cell, 96, pp. 329-339Araujo, E.P., Amaral, M.E., Souza, C.T., Bordin, S., Ferreira, F., Saad, M.J., Boschero, A.C., Velloso, L.A., Blockade of IRS1 in isolated rat pancreatic islets improves glucose-induced insulin secretion (2002) FEBS Lett., 531, pp. 437-442Araujo, E.P., Amaral, M.E., Filiputti, E., De Souza, C.T., Laurito, T.L., Augusto, V.D., Saad, M.J., Carneiro, E.M., Restoration of insulin secretion in pancreatic islets of protein-deficient rats by reduced expression of insulin receptor substrate (IRS)-1 and IRS-2 (2004) J. Endocrinol., 181, pp. 25-38Salatino, M., Schillaci, R., Proietti, C.J., Carnevale, R., Frahm, I., Molinolo, A.A., Iribarren, A., Elizalde, P.V., Inhibition of in vivo breast cancer growth by antisense oligodeoxynucleotides to type I insulin-like growth factor receptor mRNA involves inactivation of ErbBs, PI-3K/Akt and p42/p44 MAPK signaling pathways but not modulation of progesterone receptor activity (2004) Oncogene, 23, pp. 5161-5174Kubota, Y., Tanaka, T., Kitanaka, A., Ohnishi, H., Okutani, Y., Waki, M., Ishida, T., Kamano, H., Src transduces erythropoietin-induced differentiation signals through phosphatidylinositol 3-kinase (2001) EMBO J., 20, pp. 5666-5677Orike, N., Middleton, G., Borthwick, E., Buchman, V., Cowen, T., Davies, A.M., Role of PI 3-kinase, Akt and Bcl-2-related proteins in sustaining the survival of neurotrophic factor-independent adult sympathetic neurons (2001) J. Cell Biol., 154, pp. 995-1005Kim, Y.K., Han, J.W., Woo, Y.N., Chun, J.K., Yoo, J.Y., Cho, E.J., Hong, S., Lee, H.W., Expression of p21(WAF1/Cip1) through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase-PKC epsilon signaling pathway (2003) Oncogene, 22, pp. 6023-6031Kobayashi, H., Suzuki, M., Kanayama, N., Terao, T., Genetic down-regulation of phosphoinositide 3-kinase by bikunin correlates with suppression of invasion and metastasis in human ovarian cancer HRA cells (2004) J. Biol. Chem., 279, pp. 6371-6379Liu, X., Shi, Y., Han, E.K., Chen, Z., Rosenberg, S.H., Giranda, V.L., Luo, Y., Ng, S.C., Downregulation of Akt1 inhibits anchorage-independent cell growth and induces apoptosis in cancer cells (2001) Neoplasia, 3, pp. 278-286Chang, H., Shyu, K.G., Lin, S., Wang, B.W., Liu, Y.C., Lee, C.C., Cell adhesion induces the plasminogen activator inhibitor-1 gene expression through phosphatidylinositol 3-kinase/Akt activation in anchorage dependent cells (2002) Cell Commun. Adhes., 9, pp. 239-247Jonassen, A.K., Mjos, O.D., Sack, M.N., p70s6 kinase is a functional target of insulin activated Akt cell-survival signaling (2004) Biochem. Biophys. Res. Commun., 315, pp. 160-165