Immune escape of AKT overexpressing ovarian cancer cells

Hahne,Jens  C.; Meyer,Susanne  R.; Gambaryan,Stepan; Walter,Ulrich; Dietl,Johannes; Engel,Jörg  B.; Honig,Arnd

doi:10.3892/ijo.2013.1846

Immune escape of AKT overexpressing ovarian cancer cells

Authors:
- Jens C. Hahne
- Susanne R. Meyer
- Stepan Gambaryan
- Ulrich Walter
- Johannes Dietl
- Jörg B. Engel
- Arnd Honig
View Affiliations

Affiliations: Department of Gynecology, University Hospital of Würzburg, D-97080 Würzburg, Germany, Institute for Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, D-97080 Würzburg, Germany, Centre for Thrombosis and Haemostasis, University of Mainz, D-55131 Mainz, Germany, Department of Gynecology, University of Regensburg, D-93055 Regensburg, Germany
Published online on: March 4, 2013 https://doi.org/10.3892/ijo.2013.1846
Pages: 1630-1635

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Platinum-resistance is the most crucial problem for treatment of ovarian cancer. There is a clinical need for new treatment strategies which overcome platinum resistance. As survival is strongly influenced by immunological parameters, immunotherapeutic strategies appear promising. Therefore a better understanding of the interaction between ovarian tumour cells and cells of the immune system is a necessary prerequisite. In the present study we aimed to enlighten the interactions between platinum resistant and platinum sensitive ovarian cancer cells and natural-killer (NK)-cells. Modified FATAL assay was used for determining the killing efficiency of NK-cells for the parental A2780 cells and the cis-platinum resistant A2780cis human ovarian cancer cells. Expression of pro- and anti-apoptotic genes as well as ligands involved in NK-cell receptor recognition were analysed by RT-PCR and flow cytometric analysis. The efficiency of NK mediated cell lysis differs between A2780 cells and the cis-platinum-resistant A2780cis cells. A2780cis cells are less accessible for NK-cell mediated killing. Based on this observation we characterized the molecular basis for resistance mechanisms. Besides an increase in anti-apoptotic genes (especially CIAP-1 and -2) that probably render A2780cis cells more resistant against apoptosis an increased amount of soluble MICA/B seems to be responsible for the lower killing rate of platinum-resistant A2780cis cells compared to their parental A2780 cells.

View Figures

View References

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.	Lanier LL: NK cell recognition. Annu Rev Immunol. 23:225–274. 2005. View Article : Google Scholar : PubMed/NCBI
6.	Dunn GP, Bruce AT, Ikeda H, Old LJ and Schreiber RD: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 3:991–998. 2002. View Article : Google Scholar : PubMed/NCBI
7.	Orr MT and Lanier LL: Natural killer cell education and tolerance. Cell. 142:847–856. 2010. View Article : Google Scholar : PubMed/NCBI
8.	Smyth MJ, Dunn GP and Schreiber RD: Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 90:1–50. 2006. View Article : Google Scholar : PubMed/NCBI
9.	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
10.	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
11.	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
12.	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
13.	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
14.	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
15.	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 : PubMed/NCBI
16.	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
17.	Hahne JC, Honig A, Meyer SR, et al: Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro. Oncol Rep. 28:2023–2028. 2012.PubMed/NCBI
18.	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
19.	Valiante NM, Rengaraju M and Trinchieri G: Role of the production of natural killer cell stimulatory factor (NKSF/IL-12) in the ability of B cell lines to stimulate T and NK cell proliferation. Cell Immunol. 145:187–198. 1992. View Article : Google Scholar : PubMed/NCBI
20.	Sheehy ME, McDermott AB, Furlan SN, Klenerman P and Nixon DF: A novel technique for the fluorometric assessment of T lymphocytic antigen specific lysis. J Immunol Methods. 249:99–110. 2001. View Article : Google Scholar : PubMed/NCBI
21.	Jesnowski R, Backhaus C, Ringel J and Lohr M: Ribosomal highly basic 23-kDa protein as a reliable standard for gene expression analysis. Pancreatology. 2:421–424. 2002. View Article : Google Scholar : PubMed/NCBI
22.	Caligiuri MA: Human natural killer cells. Blood. 112:461–469. 2008. View Article : Google Scholar : PubMed/NCBI
23.	Vivier E, Raulet DH, Moretta A, et al: Innate or adaptive immunity? The example of natural killer cells. Science. 331:44–49. 2011. View Article : Google Scholar : PubMed/NCBI
24.	Lanier LL: Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 9:495–502. 2008. View Article : Google Scholar : PubMed/NCBI
25.	Moretta L, Biassoni R, Bottino C, Mingari MC and Moretta A: Human NK-cell receptors. Immunol Today. 21:420–422. 2000. View Article : Google Scholar : PubMed/NCBI
26.	Bellucci R, Nguyen HN, Martin A, et al: Tyrosine kinase pathways modulate tumor susceptibility to natural killer cells. J Clin Invest. 122:2369–2383. 2012. View Article : Google Scholar : PubMed/NCBI
27.	Boutet P, Agüera-Gonza’lez S, Atkinson S, et al: Cutting edge: the metalloproteinase ADAM17/TNF-α-converting enzyme regulates proteolytic shedding of the MHC class I-related chain B protein. J Immunol. 182:49–53. 2009.PubMed/NCBI
28.	Waldhauer I, Goehlsdorf D, Gieseke F, et al: Tumor-associated MICA is shed by ADAM proteases. Cancer Res. 68:6368–6376. 2008. View Article : Google Scholar : PubMed/NCBI
29.	Okita R, Mougiakakos D, Ando T, et al: HER2/HER3 signaling regulates NK cell-mediated cytotoxicity via MHC class I chain-related molecule A and B expression in human breast cancer cell lines. J Immunol. 188:2136–2145. 2012. View Article : Google Scholar : PubMed/NCBI