Editorial [Hot Topic: Akt Pathway in Oncogenesis and as a Target for Anti-Cancer Therapy (Guest Editor: Jin Q. Cheng) ]

The first evidence that AKT plays a role in carcinogenesis was provided by the isolation of the transforming retrovirus from an AKR mouse T-cell lymphoma about thirty years ago [1], which was subsequently shown to contain transduced sequences of cellular origin. In early 1990, the intact viral oncogene, v-akt, was cloned [2]. The predicted oncoprotein encoded by v-akt harbored viral Gag sequences fused to a kinase related to protein kinase C. The tumorigenic potential of the v-akt product was found to come about because of the presence of a myristylation site at its amino-terminus, with resultant translocation to the plasma membrane and constitutive kinase activity [3]. AKT is now known to have a family of three closely related cellular homologues, named AKT1, AKT2 and AKT3. All three AKT members are activated by phosphatidylinositol 3-kinase (PI3K) and inhibited by tumor suppressor PTEN [4]. Accumulated evidence indicates that AKT is a major signaling pathway that regulates cell proliferation and survival, cell growth (size), glucose metabolism, cell motility and angiogenesis [4]. Alterations of this pathway account for approximately half of various types of human malignancy. Thus, AKT presents an exciting target for molecular therapeutics. This issue of Curr Cancer Drug Targets Reviews includes perspectives on AKT normal cellular functions and biological consequences of alterations of this pathway, as well as small molecule inhibitors of AKT. Three reviews focus on AKT regulation of cellular processes and alterations of AKT in human malignancy, one of which highlights the role of major AKT substrates involved in cellular proliferation, survival, transcription and translation [5] and the other two address the role of AKT in angiogenesis [6] and deregulation of the AKT pathway in human cancer [7]. An additional article discusses current approaches to identifying selective inhibitors of the AKT [8]. [1] Staal, S. P.; Hartley, J. W.; Rowe, W. P. Effect of interferon on murine leukemia virus infection. II. Synthesis of viral components in exogenous infection. Proc. Natl. Acad. Sci. USA 1977, 74, 3065-3067. [2] Bellacosa, A.; Testa, J. R.; Staal, S. P.; Tsichlis, P. N. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2- like region. Science 1991, 254, 274-277. [3] Ahmed, N. N.; Franke, T. F.; Bellacosa, A.; Datta, K.; Gonzalez-Portal, M. E.; Taguchi, T.; Testa, J. R.; Tsichlis, P. N. The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene 1993, 8, 1957-1963. [4] Manning, B. D.; Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 2007, 129, 1261-1274. [5] Cheng, G. Z.; Park, S.; Shu, S.; He, L.; Kong, W.; Zhang, W.; Yuan, Z. Q.; Wang, L. -H.; Cheng, J. Q. Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr. Cancer Drug Targets 2008, 8(1), 2-6. [6] Jiang, B. H.; Liu, L. Z. AKT signaling in regulating angiogenesis. Curr. Cancer Drug Targets 2008, 8(1), 19-26. [7] Tokunaga, E.; Oki, E.; Egashira, A.; Sadanaga, N.; Morita, M.; Kakeji, Y.; Maehara, Y. Deregulation of the Akt pathway in human cancer. Curr. Cancer Drug Targets 2008, 8(1), 27-36. [8] Lindsley, C. W.; Barnett, S. F.; Layton, M. E.; Bilodeau, M. T. The PI3K/Akt pathway: Recent progress in the development of ATPcompetitive and allosteric Akt kinase inhibitors. Curr. Cancer Drug Targets 2008, 8(1), 7-18.