Original Article

Oncogene (2010) 29, 3519–3531; doi:10.1038/onc.2010.107; published online 19 April 2010

Ovarian cancer ascites protects from TRAIL-induced cell death through αvβ5 integrin-mediated focal adhesion kinase and Akt activation

D Lane1, N Goncharenko-Khaider1, C Rancourt1 and A Piché1

1Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada

Correspondence: Dr A Piché, Département de Microbiologie et Infectiologie, Université de Sherbrooke, 3001, 12ième Ave Nord, Sherbrooke, Québec, Canada J1H 5N4. E-mail: Alain.Piche@USherbrooke.ca

Received 28 May 2009; Revised 11 February 2010; Accepted 14 February 2010; Published online 19 April 2010.

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Abstract

Interactions between ovarian cancer cells and the surrounding tumor microenvironment are not well characterized. We have earlier shown that ovarian cancer ascites induces Akt activation and protect tumor cells from TRAIL-induced apoptosis. Here, we investigated the mechanism by which ascites activates Akt. The ability of ovarian cancer ascites to activate Akt and inhibit TRAIL-induced cell death and caspase activity was decreased by heat inactivation, but was retained in ascites fractions >5kDa. The survival promoting activity of ascites was not affected by inhibitors of growth factor receptor including epidermal growth factor receptor (EGFR), VEGFR, FGFR, Her2/neu, and IGF-R1. However, this activity was inhibited by an αvβ5 integrin-blocking antibody, but not by blocking antibodies against αvβ3, β1, or β3 integrins. αvβ5 integrin-blocking antibodies also inhibited ascites-induced Akt phosphorylation and c-FLIPs up-regulation. Ovarian cancer ascites induced a rapid phosphorylation of focal adhesion kinase (FAK), which closely correlated with the phosphorylation of Akt overtime. FAK phosphorylation was strongly inhibited by αvβ5 integrin-blocking antibodies. Depletion of FAK content by RNA interference was also associated with inhibition of ascites-mediated Akt activation and survival. These results suggest that ovarian cancer ascites induces FAK and Akt activation in an αvβ5 integrin-dependent pathway, which confers protection from TRAIL-induced cell death and caspase activation.

Keywords:

integrins; death receptors; ovarian carcinoma; ascites; PI3K/Akt pathway; TRAIL