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Article

Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro

  • Authors:
    • J. C. Hahne
    • A. Honig
    • S. R. Meyer
    • S. Gambaryan
    • U. Walter
    • J. Wischhusen
    • S. F.M. Häussler
    • S. E. Segerer
    • N. Fujita
    • J. Dietl
    • J. B. Engel
  • View Affiliations / Copyright

    Affiliations: Department of Gynecology, University of Würzburg, D-97080 Würzburg, Germany, Institute for Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, D-97080 Würzburg, Germany, The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan, Department of Gynecology, University of Regensburg, D-93055 Regensburg, Germany
  • Pages: 2023-2028
    |
    Published online on: September 18, 2012
       https://doi.org/10.3892/or.2012.2041
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Abstract

Platinum resistance is the most crucial problem for treatment of ovarian cancer. Increasing evidence points towards AKT overexpression as a mechanistic reason for this clinical condition. The present study evaluates the effect of overexpression and downregulation of AKT on the sensitivity to cisplatin in a platinum-resistant human ovarian cancer cell line and the corresponding platinum-sensitive parental cell line. A2780 and A2780cis ovarian cancer cell lines were stably transfected with an AKT-sense and AKT-antisense plasmid. Successful transfection was evaluated by western blot analysis. Cytotoxic effects of cisplatin were evaluated by metabolic (MTT) and clonogenicity assays as well as by FACS analysis. AKT overexpression (confirmed by western blotting) converted platinum-sensitive A2780 into platinum-resistant cells as shown by MTT assay. Importantly, platinum resistance of A2780cis cells could be reversed by downregulation of AKT, as demonstrated by MTT and clonogenicity assays and FACS analysis. Our data provide strong evidence that cisplatin resistance in ovarian cancer is mediated by AKT overexpression and can be overcome by AKT downregulation, thus, providing a rationale for clinical phase II/III studies combining AKT inhibitors with cisplatin.
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1 

Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar

2 

Pignata S, Cannella L, Leopardo D, Pisano C, Bruni GS and Facchini G: Chemotherapy in epithelial ovarian cancer. Cancer Lett. 303:73–83. 2011. View Article : Google Scholar

3 

Gonzalez-Martin AJ: Medical treatment of epithelial ovarian cancer. Expert Rev Anticancer Ther. 4:1125–1143. 2004. View Article : Google Scholar : PubMed/NCBI

4 

Matsuo K, Lin YG, Roman LD and Sood AK: Overcoming platinum resistance in ovarian carcinoma. Expert Opin Investig Drugs. 19:1339–1354. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Altomare DA, Wang HQ, Skele KL, et al: AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene. 23:5853–5857. 2004. View Article : Google Scholar : PubMed/NCBI

6 

Cheng JQ, Lindsley CW, Cheng GZ, Yang H and Nicosia SV: The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene. 24:7482–7492. 2005. View Article : Google Scholar : PubMed/NCBI

7 

Steelman LS, Chappell WH, Abrams SL, et al: Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging. 3:192–222. 2011.PubMed/NCBI

8 

Levine DA, Bogomolniy F, Yee CJ, et al: Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res. 11:2875–2878. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Engel JB, Schonhals T, Hausler S, et al: Induction of programmed cell death by inhibition of AKT with the alkylphosphocholine perifosine in in vitro models of platinum sensitive and resistant ovarian cancers. Arch Gynecol Obstet. 283:603–610. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Santiskulvong C, Konecny GE, Fekete M, et al: Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma. Clin Cancer Res. 17:2373–2384. 2011. View Article : Google Scholar

11 

Westfall SD and Skinner MK: Inhibition of phosphatidylinositol 3-kinase sensitizes ovarian cancer cells to carboplatin and allows adjunct chemotherapy treatment. Mol Cancer Ther. 4:1764–1771. 2005. View Article : Google Scholar

12 

Benedetti V, Perego P, Luca Beretta G, et al: Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds. Mol Cancer Ther. 7:679–687. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Sato S, Fujita N and Tsuruo T: Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci USA. 97:10832–10837. 2000. View Article : Google Scholar : PubMed/NCBI

14 

Katayama K, Fujita N and Tsuruo T: Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Mol Cell Biol. 25:5725–5737. 2005. View Article : Google Scholar : PubMed/NCBI

15 

Behrens BC, Hamilton TC, Masuda H, et al: Characterization of a cis-diamminedichloroplatinum(II)-resistant human ovarian cancer cell line and its use in evaluation of platinum analogues. Cancer Res. 47:414–418. 1987.PubMed/NCBI

16 

Engels K, Knauer SK, Loibl S, et al: NO signaling confers cytoprotectivity through the survivin network in ovarian carcinomas. Cancer Res. 68:5159–5166. 2008. View Article : Google Scholar : PubMed/NCBI

17 

Campling PJ, Galbraith PR and Cole SP: Use of the MTT assay for rapid determinarion of chemosensitivity of human leukemic blast cells. Leuk Res. 12:823–831. 1988. View Article : Google Scholar : PubMed/NCBI

18 

Hayakawa J, Ohmichi M, Kurachi H, et al: Inhibition of BAD phosphorylation either at serine 112 via extracellular signal-regulated protein kinase cascade or at serine 136 via Akt cascade sensitizes human ovarian cancer cells to cisplatin. Cancer Res. 60:5988–5994. 2000.

19 

Yang X, Fraser M, Moll UM, Basak A and Tsang BK: Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway. Cancer Res. 66:3126–3136. 2006. View Article : Google Scholar : PubMed/NCBI

20 

Fraser M, Bai T and Tsang BK: Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function. Int J Cancer. 122:534–546. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Yang X, Fraser M, Abedini MR, Bai T and Tsang BK: Regulation of apoptosis-inducing factor-mediated, cisplatin-induced apoptosis by Akt. Br J Cancer. 98:803–808. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Arafa el SA, Zhu Q, Barakat BM, et al: Tangeretin sensitizes cisplatin-resistant human ovarian cancer cells through downregulation of phosphoinositide 3-kinase/Akt signaling pathway. Cancer Res. 69:8910–8917. 2009.

23 

Kolasa IK, Rembiszewska A, Felisiak A, et al: PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients. Cancer Biol Ther. 8:21–26. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Woenckhaus J, Steger K, Sturm K, Munstedt K, Franke FE and Fenic I: Prognostic value of PIK3CA and phosphorylated AKT expression in ovarian cancer. Virchows Arch. 450:387–395. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Marsh Rde W, Rocha Lima CM, Levy DE, Mitchell EP, Rowland KM Jr and Benson AB III: A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma. Am J Clin Oncol. 30:26–31. 2007.PubMed/NCBI

26 

Leighl NB, Dent S, Clemons M, et al: A phase 2 study of perifosine in advanced or metastatic breast cancer. Breast Cancer Res Treat. 108:87–92. 2007. View Article : Google Scholar : PubMed/NCBI

27 

Snyder EL, Bailey D, Shipitsin M, Polyak K and Loda M: Identification of CD44v6(+)/CD24− breast carcinoma cells in primary human tumors by quantum dot-conjugated antibodies. Lab Invest. 89:857–866. 2009.

28 

Argiris A, Cohen E, Karrison T, et al: A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer. Cancer Biol Ther. 5:766–770. 2006. View Article : Google Scholar : PubMed/NCBI

29 

Knowling M, Blackstein M, Tozer R, et al: A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: a National Cancer Institute of Canada Clinical Trials Group trial. Invest New Drugs. 24:435–439. 2006. View Article : Google Scholar

30 

Posadas EM, Gulley J, Arlen PM, et al: A phase II study of perifosine in androgen independent prostate cancer. Cancer Biol Ther. 4:1133–1137. 2005. View Article : Google Scholar : PubMed/NCBI

31 

Ernst DS, Eisenhauer E, Wainman N, et al: Phase II study of perifosine in previously untreated patients with metastatic melanoma. Invest New Drugs. 23:569–575. 2005. View Article : Google Scholar : PubMed/NCBI

32 

Vink SR, Schellens JH, Beijnen JH, et al: Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours. Radiother Oncol. 80:207–213. 2006. View Article : Google Scholar : PubMed/NCBI

33 

He G, Kuang J, Khokhar AR and Siddik ZH: The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog. Gynecol Oncol. 122:402–409. 2011. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Hahne JC, Honig A, Meyer SR, Gambaryan S, Walter U, Wischhusen J, Häussler SF, Segerer SE, Fujita N, Dietl J, Dietl J, et al: Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro. Oncol Rep 28: 2023-2028, 2012.
APA
Hahne, J.C., Honig, A., Meyer, S.R., Gambaryan, S., Walter, U., Wischhusen, J. ... Engel, J.B. (2012). Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro. Oncology Reports, 28, 2023-2028. https://doi.org/10.3892/or.2012.2041
MLA
Hahne, J. C., Honig, A., Meyer, S. R., Gambaryan, S., Walter, U., Wischhusen, J., Häussler, S. F., Segerer, S. E., Fujita, N., Dietl, J., Engel, J. B."Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro". Oncology Reports 28.6 (2012): 2023-2028.
Chicago
Hahne, J. C., Honig, A., Meyer, S. R., Gambaryan, S., Walter, U., Wischhusen, J., Häussler, S. F., Segerer, S. E., Fujita, N., Dietl, J., Engel, J. B."Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro". Oncology Reports 28, no. 6 (2012): 2023-2028. https://doi.org/10.3892/or.2012.2041
Copy and paste a formatted citation
x
Spandidos Publications style
Hahne JC, Honig A, Meyer SR, Gambaryan S, Walter U, Wischhusen J, Häussler SF, Segerer SE, Fujita N, Dietl J, Dietl J, et al: Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro. Oncol Rep 28: 2023-2028, 2012.
APA
Hahne, J.C., Honig, A., Meyer, S.R., Gambaryan, S., Walter, U., Wischhusen, J. ... Engel, J.B. (2012). Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro. Oncology Reports, 28, 2023-2028. https://doi.org/10.3892/or.2012.2041
MLA
Hahne, J. C., Honig, A., Meyer, S. R., Gambaryan, S., Walter, U., Wischhusen, J., Häussler, S. F., Segerer, S. E., Fujita, N., Dietl, J., Engel, J. B."Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro". Oncology Reports 28.6 (2012): 2023-2028.
Chicago
Hahne, J. C., Honig, A., Meyer, S. R., Gambaryan, S., Walter, U., Wischhusen, J., Häussler, S. F., Segerer, S. E., Fujita, N., Dietl, J., Engel, J. B."Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro". Oncology Reports 28, no. 6 (2012): 2023-2028. https://doi.org/10.3892/or.2012.2041
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