Abstract
We previously demonstrated that AKT2, a member of protein kinase B family, is activated by a number of growth factors via Ras and PI 3-kinase signaling pathways. Here, we report the frequent activation of AKT2 in human primary ovarian cancer and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase (PI 3-kinase)/Akt pathway. In vitro AKT2 kinase assay analyses in 91 ovarian cancer specimens revealed elevated levels of AKT2 activity (>3-fold) in 33 cases (36.3%). The majority of tumors displaying activated AKT2 were high grade and stages III and IV. Immunostaining and Western blot analyses using a phospho-ser-473 Akt antibody that detects the activated form of AKT2 (AKT2 phosphorylated at serine-474) confirmed the frequent activation of AKT2 in ovarian cancer specimens. Phosphorylated AKT2 in tumor specimens localized to the cell membrane and cytoplasm but not the nucleus. To address the mechanism of AKT2 activation, we measured in vitro PI 3-kinase activity in 43 ovarian cancer specimens, including the 33 cases displaying elevated AKT2 activation. High levels of PI 3-kinase activity were observed in 20 cases, 15 of which also exhibited AKT2 activation. The remaining five cases displayed elevated AKT1 activation. Among the cases with elevated AKT2, but not PI 3-kinase activity (18 cases), three showed down-regulation of PTEN protein expression. Inhibition of PI 3-kinase/AKT2 by wortmannin or LY294002 induces apoptosis in ovarian cancer cells exhibiting activation of the PI 3-kinase/AKT2 pathway. These findings demonstrate for the first time that activation of AKT2 is a common occurrence in human ovarian cancer and that PI 3-kinase/Akt pathway may be an important target for ovarian cancer intervention.
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References
Alessi DR and Cohen P . 1998 Curr Opin Genet Dev 8: 55–62
Aman MJ, Lamkin TD, Okada H, Kurosaki T and Ravichandran KS . 1998 J Biol Chem 273: 33922–33928
Andjelkovic M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, Cron P, Cohen P, Lucocq JM and Hemmings BA . 1997 J Biol Chem 272: 31515–31524
Bellacosa A, Testa JR, Staal SP and Tsichlis PN . 1991 Science 254: 274–277
Bellacosa A, Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare D, Wan M, Dubeau L, Scambia G, Masciullo V, Ferrandina G, Panici PB, Mancuso S, Neri G and Testa JR . 1995 Int J Cancer 64: 280–285
Berns EMJJ, Foekens JA, van Staveren IL, van Putten WLJ, de Koning HYWCM, Portengen H and Klijin JGM . 1995 Gene 159: 11–18
Brison O . 1993 Biochim Biophys Acta 1155: 25–41
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME . 1999 Cell 96: 857–868
Burgering BMT and Coffer PJ . 1995 Nature 376: 599–602
Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S and Reed JC . 1998 Science 282: 1318–1321
Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM and Vogt PK . 1997 Science 276: 1848–1850
Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, Tsichlis PN and Testa JR . 1992 Proc Natl Acad Sci USA 89: 9267–9271
Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK and Testa JR . 1996 Proc Natl Acad Sci USA 93: 3636–3641
Cheng JQ, Altomare DA, Klein MA, Lee W-C, Mysliwiec T, Lissy NA and Testa JR . 1997 Oncogene 14: 2793–2801
Datta K, Bellacosa A, Chan TO and Tsichlis PN . 1996 J Biol Chem 271: 30835–30839
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME . 1997 Cell 91: 231–241
Delcommenne M, Tan C, Gray V, Rue L, Woodgett J and Dedhar S . 1998 Proc Natl Acad Sci USA 95: 11211–11216
del Peso L, Gonzalez-Garcia M, Page C, Herrera CR and Nunez G . 1997 Science 278: 687–689
Devilee P and Cornelisse CJ . 1994 Biochim Biophys Acta 1198: 113–130
Du K and Montminy M . 1998 J Biol Chem 273: 32377–32379
Franke TF, Yang SL, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR and Tsichlis PN . 1995 Cell 81: 727–736
Jiang K, Coppola D, Crespo NC, Nicosia SV, Hamilton AD, Sebti SM and Cheng JQ . 2000 Mol Cell Biol 20: 139–148
Jimenez C, Jones DR, Rodriguez-Viciana P, Gonzalez-Garcia A, Leonardo E, Wennstrom S, von Kobbe C, Toran JL, R-Borlado L, Calvo V, Copin SG, Albar JP, Gaspar ML, Diez E, Marcos MA, Downward J, Martinez-A C, Merida I and Carrera AC . 1998 EMBO J 17: 743–753
Jones PF, Jakubowicz T, Pitossi FJ, Maurer F and Hemmings BA . 1991a Proc Natl Acad Sci USA 88: 4171–4175
Jones PF, Jakubowicz T and Hemmings BA . 1991b Cell Reg 2: 1001–1009
Klippel A, Escobedo JA, Hu Q and Williams LT . 1993 Mol Cell Biol 13: 5560–5566
Konishi H, Kuroda S, Tanaca M, Ono Y, Kameyama K, Haga T and Kikkawa U . 1995 Biochem Biophys Res Commun 216: 526–534
Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL and Burgering BM . 1999 Nature 398: 630–634
Liu A-X, Testa JR, Hamilton TC, Jove R, Nicosia SV and Cheng JQ . 1998 Cancer Res 58: 2973–2977
McMenamin ME, Soung P, Perera S, Kaplan I, Loda M and Sellers WR . 1999 Cancer Res 59: 4291–4296
Meier R, Alessi DR, Cron P, Andjelkovic M and Hemmings BA . 1997 J Biol Chem 272: 30491–30497
Nakatani K, Sakaue H, Thompson DA, Weigel RJ and Roth RA . 1999 Biochem Biophys Res Commun 257: 906–910
Obata K, Morland SJ, Watson RH, Hitchcock A, Chenevix-Trench G, Thomas EJ and Campbell IG . 1998 Cancer Res 58: 2095–2097
Phillips WA, St Clair F, Munday AD, Thomas RJ and Mitchell CA . 1998 Cancer 83: 41–47
Ruggeri B, Huang L, Wood M, Cheng JQ and Testa JR . 1998 Mol Carcinogenesis 21: 81–86
Shaw M, Cohen P and Alessi DR . 1998 Biochem J 336: 241–246
Shayesteh L, Lu YL, Kuo WL, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB and Gray JW . 1999 Nature Genet 21: 99–102
Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP and Mak TW . 1998 Cell 95: 29–39
Wu X, Senechal K, Neshat MS, Whang YE and Sawyers CL . 1998 Proc Natl Acad Sci USA 95: 15587–15591
Acknowledgements
We are grateful to Dr Sue A Shelley for critical reading and comments on the manuscript; June E Paciga, and Jie-liu Tang for technical support. We are also grateful for Tissue Procurement, DNA Sequence and Tissue Pathology Core Facilities at H Lee Moffitt Cancer Center for providing cancer specimens, sequencing and immunohistochemical staining. This work was supported by National Cancer Institute Grant CA77935 (to JQ Cheng) and University of South Florida Ovarian Cancer Pathobiology Grant 6115-000-20 (to SV Nicosia).
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Yuan, Z., Sun, M., Feldman, R. et al. 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 (2000). https://doi.org/10.1038/sj.onc.1203598
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DOI: https://doi.org/10.1038/sj.onc.1203598
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