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Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2018

Open Access 01-12-2018 | Research

Mitochondrial membrane depolarization enhances TRAIL-induced cell death in adult human granulosa tumor cells, KGN, through inhibition of BIRC5

Authors: Julie A. MacDonald, Niharika Kura, Carleigh Sussman, Dori C. Woods

Published in: Journal of Ovarian Research | Issue 1/2018

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Abstract

Background

Cellular metabolic changes that accompany malignant transformation have been heralded as hallmark features of cancer. However, metabolic signatures between neoplasms can be unique, allowing for distinctions in malignancy, invasion and chemoresistance between cancer types and subtypes. Mitochondria are central metabolic mediators, as cellular bioenergetics veers from oxidative phosphorylation to glycolysis. Herein, we evaluate the role of mitochondria in maintenance of cellular metabolism, proliferation, and survival in the adult granulosa tumor cell line, KGN, as well as three epithelial ovarian cancer cell lines to determine distinctions in specific features.

Results

Notably, KGN cells were susceptible to TRAIL- and cisplatin-induced death following pretreatment with the metabolic inhibitor FCCP, but not oligomycin A. Collapse of mitochondrial membrane potential was found concomitant with cell death via apoptosis, independent from extrinsic canonical apoptotic routes. Rather, treatment with FCCP resulted in elevated cytochrome c release from mitochondria and decreased responsiveness to BIRC5. Following knockdown of BIRC5, mitochondrial membrane depolarization further sensitized KGN cells to induction of apoptosis via TRAIL.

Conclusions

These results indicate an essential role, distinct from metabolism, for mitochondrial membrane potential in KGN cells to sense and respond to external mediators of apoptotic induction.
Appendix
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Literature
1.
Truman AM, Johnson AL, Woods DC. Granulosa Cell Tumors. In: Schwab M, editor. Encyclopedia of Cancer. 4th revise. Berlin: Springer-Verlag Berlin and Heidelberg GmbH & co.; 2016.
2.
Shah S, Köbel M, Senz J, Morin R, Clarke B, Wiegand K, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med. 2009;360(26):2719–29.CrossRefPubMed
3.
Leung D, Fuller P, Chu S. Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors. Int J Biochem Cell Biol. 2016;72:51–4.CrossRefPubMed
4.
Jamieson S, Fuller PJ. Molecular pathogenesis of granulosa cell tumors of the ovary. Endocr Rev. 2012;33(1):109–44.CrossRefPubMed
5.
Köbel M, Gilks C, Huntsman D. Adult-type granulosa cell tumors and FOXL2 mutation. Cancer Res. 2009;69(24):9160–2.CrossRefPubMed
6.
7.
Colombo N, Parma G, Zanagnolo V, Insinga A. Management of ovarian stromal cell tumors. J Clin Oncol. 2007;25(20):2944–51.CrossRefPubMed
8.
Segal R, DePetrillo AD, Thomas G. Clinical review of adult granulosa cell tumors of the ovary. Gynecol Oncol. 1995;56:338–44.CrossRefPubMed
9.
Miller K, McCluggage WG. Prognostic factors in ovarian adult granulosa cell tumour. J Clin Pathol. 2008;61(8):881–4.CrossRefPubMed
10.
Vander Heiden MG, Cantley LC, Thompson CB, Mammalian P, Exhibit C, Metabolism A. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.CrossRefPubMedPubMedCentral
11.
Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11(5):325–37.CrossRefPubMed
12.
Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891.CrossRefPubMed
13.
Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007;11(1):37–51.CrossRefPubMed
14.
Schmidt M, Kammerer U, Segerer S, Cramer A, Kohrenhagen N, Dietl J, Voelker H. Glucose metabolism and angiogenesis in granulosa cell tumors of the ovary: activation of Akt, expression of M2PK, TKTL1 and VEGF. Eur J Obstet Gynecol Reprod Biol. 2008;139(1):72–8.CrossRefPubMed
15.
Dier U, Shin DH, Hemachandra LMP, Uusitalo LM, Hempel N. Bioenergetic analysis of ovarian cancer cell lines: profiling of histological subtypes and identification of a mitochondria-defective cell line. PLoS One. 2014;9(5):e98479.CrossRefPubMedPubMedCentral
16.
Xintaropoulou C, Ward C, Wise A, Marston H, Turnbull A, Langdon SP. A comparative analysis of inhibitors of the glycolysis pathway in breast and ovarian cancer cell line models. Oncotarget. 2015;6(28):25677–95.CrossRefPubMedPubMedCentral
17.
Sun L, Yin Y, Clark LH, Sun W, Sullivan SA, Tran AQ, et al. Dual inhibition of glycolysis and glutaminolysis as a therapeutic strategy in the treatment of ovarian cancer. Oncotarget. 2017;8(38):63551–61.PubMedCentralPubMed
18.
Woods DC, Liu HK, Nishi Y, Yanase T, Johnson AL. Inhibition of proteasome activity sensitizes human granulosa tumor cells to TRAIL-induced cell death. Cancer Lett. 2008;260(1):20–7.CrossRefPubMed
19.
Woods DC, Alvarez C, Johnson AL. Cisplatin-mediated sensitivity to TRAIL-induced cell death in human granulosa tumor cells. Gynecol Oncol. 2008;108(3):632–40.CrossRefPubMed
20.
Johnson AL, Ratajczak C, Haugen MJ, Liu HK, Woods DC. Tumor necrosis factor-related apoptosis inducing ligand expression and activity in hen granulosa cells. Reproduction. 2007;133(3):609–16.CrossRefPubMed
21.
Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer. 2002;2(6):420–30.CrossRefPubMed
22.
Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995;81(4):505–12.CrossRefPubMed
23.
24.
Deveraux Q, Roy N, Stennicke H, Van Arsdale T, Zhou Q, Srinivasula S, et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 1998;17(8):2215–23.CrossRefPubMedPubMedCentral
25.
Sah NK, Khan Z, Khan GJ, Bisen PS. Structural, functional and therapeutic biology of survivin. Cancer Lett. 2006;244(2):164–71.CrossRefPubMed
26.
Ausserlechner MJ, Hagenbuchner J. Mitochondrial survivin–an Achilles’ heel in cancer chemoresistance. Mol Cell Oncol. 2016;3(2):e1076589.CrossRefPubMed
27.
Benz R, McLaughlin S. The molecular mechanism of action of the proton ionophore FCCP (carbonylcyanide p-trifluoromethoxyphenylhydrazone). Biophys J. 1983;41(3):381–98.CrossRefPubMedPubMedCentral
28.
Lane D, Côté M, Grondin R, Couture M, Piché A. Acquired resistance to TRAIL-induced apoptosis in human ovarian cancer cells is conferred by increased turnover of mature caspase-3. Mol Cancer Ther. 2006;5(3):509–21.CrossRefPubMed
29.
O’brien J, Wilson I, Orton T, Pognan F. Investigation of the Alamar blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. FEBS J. 2000;267(17):5421–6.
30.
Raspagliesi F, Martinelli F, Grijuela B, Guadalupi V. Third-line chemotherapy with tyrosine kinase inhibitor (imatinib mesylate) in recurrent ovarian granulosa cell tumor: case report. J Obstet Gynaecol Res. 2011;37(12):1864–7.CrossRefPubMed
31.
Penefsky HS. Mechanism of inhibition of mitochondrial adenosine triphosphatase by dicyclohexylcarbodiimide and oligomycin: relationship to ATP synthesis. Proc Natl Acad Sci. 1985;82(6):1589–93.CrossRefPubMedPubMedCentral
32.
Miyazawa M, Yasuda M, Fujita M, Hirabayashi K, Hirasawa T, Kajiwara H, Muramatsu T, et al. Granulosa cell tumor with activated mTOR-HIF-1α-VEGF pathway. J Obstet Gynaecol Res. 2010;36(2):448–53.CrossRefPubMed
33.
Tsoi M, Laguëëlle MN, Boyer A, Paquet M, Nadeau MÈ, Boerboom D. Anti-VEGFA therapy reduces tumor growth and extends survival in a murine model of ovarian granulosa cell tumor. Transl Oncol. 2013;6(3):226–33.CrossRefPubMedPubMedCentral
34.
Nishi Y, Yanase T, Mu YM, Oba K, Ichino I, Saito M, et al. Establishment and characterization of a steroidogenic human granulosa-like tumor cell line, KGN, that expresses functional follicle-stimulating hormone receptor. Endocrinology. 2001;142(1):437–45.CrossRefPubMed
35.
Domcke S, Sinha R, Levine DA, Sander C, Schultz N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun. 2013;4:2126.CrossRefPubMed
36.
Hernandez L, Kim MK, Lyle LT, Bunch KP, House CD, Ning F, et al. Characterization of ovarian cancer cell lines as in vivo models for preclinical studies. Gynecol Oncol. 2016;142(2):332–40.CrossRefPubMedPubMedCentral
37.
Beaufort CM, Helmijr JC, Piskorz AM, Hoogstraat M, Ruigrok-Ritstier K, Besselink N, et al. Ovarian cancer cell line panel (OCCP): clinical importance of in vitro morphological subtypes. PLoS One. 2014;9(9):e103988.CrossRefPubMedPubMedCentral
Metadata
Title
Mitochondrial membrane depolarization enhances TRAIL-induced cell death in adult human granulosa tumor cells, KGN, through inhibition of BIRC5
Authors
Julie A. MacDonald
Niharika Kura
Carleigh Sussman
Dori C. Woods
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2018
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/s13048-018-0463-3

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