Cancer Letters
Volume 246, Issue 1 , Pages 190-200 , 8 February 2007

Specific inhibition of AKT2 by RNA interference results in reduction of ovarian cancer cell proliferation: Increased expression of AKT in advanced ovarian cancer

  • Aurelia Noske

      Affiliations

    • Institute of Pathology, Charité University Hospital Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49 30 450536033; fax: +49 30 450536900.
    • ,
  • Alexander Kaszubiak

      Affiliations

    • Institute of Pathology, Charité University Hospital Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany
    • ,
  • Wilko Weichert

      Affiliations

    • Institute of Pathology, Charité University Hospital Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany
    • ,
  • Christine Sers

      Affiliations

    • Institute of Pathology, Charité University Hospital Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany
    • ,
  • Silvia Niesporek

      Affiliations

    • Institute of Pathology, Charité University Hospital Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany
    • ,
  • Ines Koch

      Affiliations

    • Institute of Pathology, Charité University Hospital Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany
    • ,
  • Birgit Schaefer

      Affiliations

    • Institute of Pathology, Charité University Hospital Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany
    • ,
  • Jalid Sehouli

      Affiliations

    • Department of Gynecology and Obstetrics, Charité University Hospital Berlin, Berlin, Germany
    • ,
  • Manfred Dietel

      Affiliations

    • Institute of Pathology, Charité University Hospital Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany
    • ,
  • Herman Lage

      Affiliations

    • Institute of Pathology, Charité University Hospital Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany
    • ,
  • Carsten Denkert

      Affiliations

    • Institute of Pathology, Charité University Hospital Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany

Received 13 February 2006 ,Revised 13 February 2006 ,Accepted 20 February 2006.

References 

  1. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al. Cancer statistics. CA Cancer J. Clin. 2004;54:8–29
  2. 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
  3. Coffer PJ, Woodgett JR. Molecular cloning and characterization of a novel putative protein–serine kinase related to the cAMP-dependent and protein kinase C families. Eur J. Biochem. 1991;201:475–481
  4. Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, 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
  5. Liu AX, Testa JR, Hamilton TC, Jove R, Nicosia SV, Cheng JQ. AKT2, a member of the protein kinase B family, is activated by growth factors, v-Ha-ras, and v-src through phosphatidylinositol 3-kinase in human ovarian epithelial cancer cells. Cancer Res. 1998;58:2973–2977
  6. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999;13:2905–2927
  7. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B alpha. Curr. Biol. 1997;7:261–269
  8. Yuan ZQ, Sun M, Feldmann RI, Wang G, Ma X, Jiang C, 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
  9. Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT—a major therapeutic target. Biochim. Biophys. Acta C. 2004;1697:3–16
  10. Cardone MH, Roy N, Stennicke HR, Salvasen GS, Franke TF, Stanbridge E, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998;282:1318–1321
  11. Kane LP, Shapiro VS, Stokoe D, Weiss A. Induction of NF-kappaB by the Akt/PKB kinase. Curr. Biol. 1999;9:601–604
  12. Gao N, Flynn DC, Zhang Z, Zhong XS, Walker V, Liu KJ, et al. 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;287:C281–C291
  13. Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer. 1995;64:280–285
  14. Zinda MJ, Johnson MA, Paul JD, Horn C, Konicek BW, Lu ZH, et al. AKT-1, -2, and -3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon. Clin. Cancer Res. 2001;7:2475–2479
  15. Ruggeri BA, Huang L, Wood M, Cheng JQ, Testa JR. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol. Carcinog. 1998;21:81–86
  16. Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, et al. Amplification of AKT2 in human pancreatic cancer cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl Acad. Sci. USA. 1996;93:3636–3641
  17. 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
  18. Vasko V, Saji M, Hardy E, Kruhlak M, Larin A, Savchenko V, et al. Akt activation and localization correlate with tumour invasion and oncogene expression in thyroid cancer. J. Med. Genet. 2004;41:161–170
  19. Shimizu Y, Kamoi S, Amada S, Hasumi K, Akiyama F, Silverberg SG. Toward the development of a universal grading system for ovarian epithelial carcinoma. Gynecol. Oncol. 1998;70:2–12
  20. Denkert C, Fürstenberg A, Daniel PT, Koch I, Köbel M, Weichert W, et al. Induction of G0/G1 cell cycle arrest in ovarian carcinoma cells by the anti-inflammatory drug NS-398, but not by COX-2-specific RNA interference. Oncogene. 2003;22:8653–8661
  21. Denkert C, Köbel M, Pest S, Koch I, Berger S, Schwabe M, et al. Expression of Cyclooxygenase 2 is an independent prognostic factor in human ovarian carcinoma. Am J. Pathol. 2002;160:893–903
  22. Tsao SW, Mok SC, Fey EG, Fletcher JA, Wan TS, Chew EC, et al. Characterization of human ovarian surface epithelial cells immortalized by human papilloma viral oncogenes (HPV-E6E7 ORFs). Exp. Cell Res. 1995;218:499–507
  23. Amin AR, Ichigotani Y, Oo ML, Biswas MH, Huang P, Mon NN, et al. The PLC-PKC cascade is required for il−1beta-dependent Erk and Akt activation: their role in proliferation. Int. J. Oncol. 2003;23:1727–1731
  24. Li L, Sampat K, Hu N, Zakari J, Yuspa SH. Protein Kinase C negatively regulates Akt activity and modifies UVC-induced apoptosis in mouse keratinocytes. J. Biol. Chem. 2005;281:3237–3243
  25. Nieth C, Priebsch A, Stege A, Lage H. Modulation of the classical multidrug resistance (MDR) phenotype by RNA interference (RNAi). Fed. Eur. Biochem. Soc. Lett. 2003;545:144–150
  26. Kowalski P, Surowiak P, Lage H. Reversal of different drug-resistant phenotypes by an autocatalytic multitarget multiribozyme directed against the transcripts of the ABC transporters MDR1/P-gp, MRP2, and BCRP. Mol. Ther. 2005;11:508–522
  27. Elbashir SM, Harborth J, Weber K, Tuschl T. Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods. 2002;26:199–221
  28. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411:494–498
  29. Vlahos CJ, Matter WF, Hui KY, Brown RF. A specific inhibitor of phosphatidyl-inositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem. 1994;269:5241–5248
  30. Czauderna F, Fechtner M, Aygun H, Arnold W, Klippel A, Giese K, et al. Functional studies of the PI(3)-kinase signalling pathway employing synthetic and expressed siRNA. Nucleic Acids Res. 2003;31:670–682
  31. Lynch HT, Casey MJ, Lynch J, White TE, Godwin AK. Genetics and ovarian carcinoma. Semin. Oncol. 1998;25:265–280
  32. Sun M, Wang G, Paciga JE, Feldman RI, Yuan ZQ, Ma XL, et al. AKT1/PKBα 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
  33. Altomare DA, Wang HQ, Skele KL, Rienzo AD, Klein-Szanto A, Godwin AK, et al. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene. 2004;23:5853–5857
  34. 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
  35. Schliemann MG, Fahy BN, Ramsamooj R, Beckett L, Bold RJ. Incidence, mechanism, and prognostic value of activated AKT in pancreas cancer. Br J. Cancer. 2003;89:2110–2115
  36. Malik SN, Brattain M, Ghosh PM, Troyer DA, Prihoda T, Bedolla R, et al. Immunohistochemical demonstration of phospho-AKT in high Gleason grade prostate cancer. Clin. Cancer Res. 2002;4:1168–1171
  37. Perez-Tenorino G. Stal O and members of the southeast Sweden breast cancer group. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J. Cancer. 2002;86:540–545
  38. Cappuzzo F, Magrini E, Ceresoli GL, Bartolini S, Rossi E, Ludovini V, et al. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J. Natl Cancer Inst. 2004;96:1133–1141
  39. Khor TO, Gul YA, Ithnin H, Seow HF. Positive correlation between overexpression of phosphor-BAD with phosphorylated Akt at serine 473 but not threonine 308in colorectal carcinoma. Cancer Lett. 2004;210:139–150
  40. Nakatani K, Sakaue H, Thompson DA, Weigel RJ, Roth RA. Identification of a human AKT3 (protein kinase B γ) which contains the regulatory serine phosphorylation site. Biochem. Biophys. Res. Commun. 1999;257:906–910
  41. Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ, et al. Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J. Biol. Chem. 1999;274:21528–21532
  42. Meier R, Alessi DR, Cron P, Andjelkovic M, Hemmings BA. Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase B beta. J. Biol. Chem. 1997;272:30491–30497
  43. Bae SS, Cho H, Mu J, Birnbaum MJ. Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J. Biol. Chem. 2003;278:49530–49536
  44. Jiang ZY, Zhou QL, Coleman KA, Chouinard M, Boese Q, Czech MP. Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc. Natl Acad. Sci. USA. 2003;100:7569–7574
  45. Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE, Ayala R, et al. Overexpression of AKT2/protein kinase B beta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res. 2003;63:196–206
  46. Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, et al. PIK3CA is implicated as a oncogene in ovarian cancer. Nat. Genet. 1999;21:99–102
  47. Page C, Lin HJ, Jin Y, Castle VP, Nunez G, Huang M, et al. Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res. 2000;20:407–416
  48. Fraser M, Leung BM, Yan X, Dan HC, Cheng JQ, Tsang BK. p53 is a determinant of x-linked inhibitor of apoptosis protein/Akt-mediated chemoresistence in human ovarian cancer cells. Cancer Res. 2003;63:7081–7088
  49. Asselin E, Mills GB, Tsang BK. XIAP regulates AKT activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer Res. 2001;61:1862–1868
  50. Vara JAF, Casado E, Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/AKT signaling pathway and cancer. Cancer Treat. Res. 2004;30:193–204
  51. Chan S. Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br. J. Cancer. 2004;91:1420–1424
  52. Hsu AL, Ching TT, Wang DS, Song X, Rangnekar VM, Chen CS. The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J. Biol. Chem. 2000;275:11397–11403
  53. Basu GD, Pathangey LB, Tinder TL, LaGioia M, Gendler SJ, Mukherjee P. COX-2 Inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer. Mol. Cancer Res. 2004;2:1–11

PII: S0304-3835(06)00124-8

doi: 10.1016/j.canlet.2006.02.018

Cancer Letters
Volume 246, Issue 1 , Pages 190-200 , 8 February 2007

Article Tools

* Image Usage & Resolution