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Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2013

Open Access 01-12-2013 | Research

Osteoprotegerin (OPG) activates integrin, focal adhesion kinase (FAK), and Akt signaling in ovarian cancer cells to attenuate TRAIL-induced apoptosis

Authors: Denis Lane, Isabelle Matte, Claude Laplante, Perrine Garde-Granger, Claudine Rancourt, Alain Piché

Published in: Journal of Ovarian Research | Issue 1/2013

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Abstract

Background

Resistance to apoptosis is a major problem in ovarian cancer (OC) and correlates with poor prognosis. Osteoprotegerin (OPG) is a soluble secreted factor that acts as a decoy receptor for receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). OPG has been reported to attenuate TRAIL-induced apoptosis in a variety of cancer cells, including OC cells. OPG-mediated protection against TRAIL has been attributed to its decoy receptor function. However, OPG activates integrin/focal adhesion kinase (FAK) signaling in endothelial cells. In OC cells, activation of integrin/FAK signaling inhibits TRAIL-induced apoptosis. Based on these observations, we hypothesized that OPG could attenuate TRAIL-induced apoptosis in OC cells through integrin/FAK signaling.

Methods

In vitro experiments including immunoblots, colony formation assays, and apoptosis measurements were used to assess the effect of OPG on TRAIL-induced apoptosis.

Results

Exogenous OPG protected from TRAIL-induced apoptosis in a TRAIL binding-independent manner and OPG protection was αvβ3 and αvβ5 integrin/FAK signaling-dependent. Moreover, OPG-mediated activation of integrin/FAK signaling resulted in the activation of Akt. Inhibition of both integrin/FAK and Akt signaling significantly inhibited OPG-mediated attenuation of TRAIL-induced apoptosis. Although OPG also stimulated ERK1/2 phosphorylation, inhibition of ERK1/2 signaling did not significantly altered OPG protection.

Conclusions

Our studies provide evidence, for the first time, that OPG can attenuate TRAIL-induced apoptosis in a TRAIL binding-independent manner through the activation of integrin/FAK/Akt signaling in OC cells.
Appendix
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Literature
1.
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ: Osteoprotegerin: a novel secreted protein involved in the regulation bone density. Cell 1997, 89: 309–319.PubMedCrossRef
2.
Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, Kanno T, Murakami A, Tsuda E, Morinaga T, Higashio K: Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 1998, 139: 1329–1337.PubMed
3.
Dougall WC: Molecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis. Clin Cancer Res 2012, 18: 326–335.PubMedCrossRef
4.
Vidal K, Serrant P, Schlosser B, van der Broek P, Lorget F, Donnet-Hughes A: Osteoprotegerin production by human intestinal cells: a potential regulator of mucosal immune responses. Am J Physiol Gastrointes Liver Physiol 2004, 287: G836-G844.CrossRef
5.
Reid PE, Brown NJ, Holen I: Breast cancer cells stimulate osteoprotegerin (OPG) production by endothelial cells through direct cell contact. Mol Cancer 2009, 8: 49.PubMedCentralPubMedCrossRef
6.
Malyankart UM, Scatena M, Suchland KL, Yun TJ, Clark EA, Giachelli CM: Osteoprotegerin is an αvβ3-induced, NF-κB-dependent survival factor for endothelial cells. J Biol Chem 2000, 275: 20959–20962.CrossRef
7.
Kobayashi-Sakamoto M, Isogai E, Hirose K, Chiba I: Role of αv integrin in osteoprotegerin-induced endothelial cell migration and proliferation. Microvasc Res 2008, 76: 139–144.PubMedCrossRef
8.
Kobayashi-Sakamoto M, Isogai E, Holen I: Osteoprotegerin induces cytoskeletal reorganization and activates FAK, Src, and ERK signaling in endothelial cells. Eur J Haematol 2010, 85: 26–35.PubMed
9.
McGonigle JS, Giachelli CM, Scatena M: Osteoprotegerin and RANKL differentially regulate angiogenesis and endothelial cell function. Angiogenesis 2009, 12: 35–46.PubMedCrossRef
10.
Benslimane-Ahmim Z, Poirier F, Delomenie C, Lokajczyk A, Grelact F, Galy-Fauroux I, Mohamedi A, Fischer AM, Heymann D, Lutomski D, Boisson-Vidal C: Mechanistic study of the proangiogenic effect of osteoprotegerin. Angiogenesis 2013, 16: 575–593.PubMedCrossRef
11.
Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR: Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998, 273: 14363–14367.PubMedCrossRef
12.
Truneh A, Sharma S, Silverman C, Khandekar S, Reddy MP, Deen KC, McLaughlin MM, Srinivasula SM, Livi GP, Marshall LA, Alnemri ES, Williams WV, Doyle ML: Temperature-sensitive differential affinity of TRAIL for its receptors. J Biol Chem 2000, 275: 23319–23325.PubMedCrossRef
13.
Abdulghani J, El‒Deiry WS: TRAIL receptor signaling and therapeutics. Expert Opin Ther Targets 2010, 14: 1091–1108.PubMedCrossRef
14.
Goncharenko-Khaider N, Lane D, Matte I, Rancourt C, Piché A: Targeted ovarian cancer treatment: the TRAILs of resistance. Am J Cancer Res 2012, 2: 75–92.
15.
Goncharenko-Khaider N, Lane D, Matte I, Rancourt C, Piché A: The inhibition of Bid expression by Akt leads to resistance to TRAIL-induced apoptosis in ovarian cancer cells. Oncogene 2010, 29: 5523–5536.PubMedCentralPubMedCrossRef
16.
Holen I, Croucher PI, Hamdy FC, Eaton CL: Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. Cancer Res 2002, 62: 1619–1623.PubMed
17.
Corey E, Brown LG, Kiefer JA, Quinn JE, Pitts TE, Blair JM, Vessella RL: Osteoprotegerin in prostate cancer bone metastasis. Cancer Res 2005, 65: 1710–1718.PubMedCrossRef
18.
Shipman CM, Croucher PI: Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells. Cancer Res 2003, 63: 912–916.PubMed
19.
Neville-Webbe HL, Cross NA, Eaton CL, Nyambo R, Evans CA, Coleman RE, Holen I: Osteoprotegerin (OPG) produced by bone marrow stromal cells protects breast cancer cells from TRAIL-induced apoptosis. Breast Cancer Res Treat 2004, 86: 269–279.PubMedCrossRef
20.
Holen I, Cross SS, Neville-Webbe HL, Cross NA, Balasubramanian SP, Croucher PI, Evans CA, Lippitt JM, Coleman RE, Eaton CL: Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo – a role in tumour cell survival? Breast Cancer Res Treat 2005, 92: 207–215.PubMedCrossRef
21.
Fisher JL, Thomas-Mudge RJ, Elliott J, Hards DK, Sims NA, Slavin J, Martin TJ, Gillespie MT: Osteoprotegerin overexpression by breast cancer cells enhances orthotopic and osseous tumor growth and contrasts with that delivered therapeutically. Cancer Res 2006, 66: 3620–3628.PubMedCrossRef
22.
Rachner TD, Benad P, Rauner M, Goettsch C, Singh SK, Schoppet M, Hofbauer LC: Osteoprotegerin production by breast cancer cells is suppressed by dexamethasone and confers resistance against TRAIL-induced apoptosis. J Cell Biochem 2009, 108: 106–116.PubMedCrossRef
23.
De Toni EN, Thieme SE, Herbst A, Behrens A, Stieber P, Jung A, Blum H, Göke B, Kolligs FT: OPG is regulated by beta-catenin and mediates resistance to TRAIL-induced apoptosis in colon cancer. Clin Cancer Res 2008, 14: 4713–4718.PubMedCrossRef
24.
Lane D, Matte I, Rancourt C, Piché A: Osteoprotegerin (OPG) protects ovarian cancer cells from TRAIL-induced apoptosis but does not contribute to malignant ascites-mediated attenuation of TRAIL-induced apoptosis. J Ovarian Res 2012, 5: 34.PubMedCentralPubMedCrossRef
25.
Cross SS, Yang Z, Brown NJ, Balasubramanian SP, Evans CA, Woodward JK, Neville-Webbe HL, Lippitt JM, Reed MW, Coleman RE, Holen I: Osteoprotegerin (OPG)-a potential new role in the regulation of endothelial cell phenotype and tumour angiogenesis? Int J Cancer 2006, 118: 1901–1908.PubMedCrossRef
26.
Lane D, Goncharenko-Khaider N, Rancourt C, Piché A: Ovarian cancer ascites protects from TRAIL-induced cell death through αvβ5 integrin-mediated focal adhesion kinase and Akt activation. Oncogene 2010, 29: 3519–3531.PubMedCrossRef
27.
Goncharenko-Khaider N, Matte I, Lane D, Rancourt C, Piché A: Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis. Mol Cancer 2012, 11: 84.PubMedCentralPubMedCrossRef
28.
Lane D, Cartier A, L’Espérance S, Côté M, Rancourt C, Piché A: Differential induction of apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in human ovarian carcinoma cells. Gynecol Oncol 2004, 93: 594–604.PubMedCrossRef
29.
Stupack DG, Cheresh DA: Get a ligand, get a life: integrins, signalling and cell survival. J Cell Science 2002, 115: 3729–3734.PubMedCrossRef
30.
Cannistra SA, Ottensmeier C, Niloff J, Orta B, DiCarlo J: Expression and function of β1 and αvβ3 integrins in ovarian cancer. Gynecol Oncol 1995, 58: 216–225.PubMedCrossRef
31.
Lane D, Robert V, Grondin R, Rancourt C, Piché A: Malignant ascites protect against TRAIL-induced apoptosis by activating the PI3K/Akt pathway in human ovarian cancer cells. Int J Cancer 2007, 121: 1227–1237.PubMedCrossRef
32.
Mao Y, Xu J, Song G, Zhang N, Yin H: Twist2 promotes ovarian cancer cell survival through activation of Akt. Oncol Lett 2013, 6: 169–174.PubMedCentralPubMed
33.
Metadata
Title
Osteoprotegerin (OPG) activates integrin, focal adhesion kinase (FAK), and Akt signaling in ovarian cancer cells to attenuate TRAIL-induced apoptosis
Authors
Denis Lane
Isabelle Matte
Claude Laplante
Perrine Garde-Granger
Claudine Rancourt
Alain Piché
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2013
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/1757-2215-6-82

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