The Salt Inducible Kinase 2 (Sik2) Links Lipid Metabolism To Survival Of Ovarian Cancer Metastasis

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PABackground:High Grade Serous Ovarian Cancer (HGSOC) metastatic disease is strongly dependent on the adipocyte-rich microenvironment of the omentum. Altough previous work has shown that adipocytes are required for driving cancer metastasis to fat-rich environments, the mechanisms involved in the process of linking metabolism to cancer cell survival at this niche have remained poorly understood and this has, therefore, hindered therapeutic exploitation. We have previously shown that the expression of the Salt Inducible Kinase 2 (SIK2) is important for ovarian cancer cell survival and that it correlates with poor patient survival (Ahmed et al., Cancer Cell, 2010). In this work we present a previously unrecognised role for SIK2 in driving cancer cell metabolism and proliferation at the omental metastatic niche.Methods:We established a system for the co-culture of cancer cells with adipocytes obtained from freshly excised normal omentum from women undergoing surgical staging. This system was used in combination with a chemical biology approach utilizing cells expressing gate-keeper mutants of SIK2 and a type I kinase inhibitor to test the specificity of observed phenotypic effects. Our results were validated using immunohistochemistry of a panel of ovarian cancers and a xenograft model of ovarian cancer metastasis.Results:SIK2 was significantly overexpressed in omental metastases of ovarian tumours compared to paired ovarian cancer primary lesions from the same patients. In a xenograft model of ovarian cancer metastasis SIK2-overexpressing cells implanted orthotopically at the ovarian bursa formed significantly larger omental metastases compared to cells with endogenous levels of SIK2. We first observed that co-culture of ovarian cancer cells with adipocytes resulted in an increased SIK2 autophosphorylation and activation which, in turn stimulated cancer cell proliferation. Next, we showed that PLC-dependent activation of calcium release was required for adipocyte-induced SIK2 autophosphorylation in ovarian cancer cells. Surprisingly, we identified a role for adipocyte-activated SIK2 in stimulating cancer cell metabolism throught augmenting AMPK-induced phosphorylation of ACC and activation of carnitine palmitoyltransferase 1 (CPT1) transcription. Concurrently, SIK2 was required to activate the PI3K complex through direct p85α-S154 phosphorylation. This was confirmed using rapamycin as a known robust paradoxical PI3K activator showing that SIK2 siRNA-mediated depletion or its chemical inhibition abolished rapamycin-induced AKT phosphorylation and sensitized ovarian cancer cells to its cytotoxic effect.Conclusion:Our results suggested that SIK2 phosphorylation and activation were required to establish ovarian cancer lesions at the adipocyte-rich omental environment. Therefore we suggest a therapeutic role for targeting SIK2 in preventing ovarian cancer metastases.Citation Format: Fabrizio Miranda, Shujuan Liu, Sandra Herrero-Gonzalez, David Mannion, Stefan Knapp, Ahmed A. Ahmed. The salt inducible kinase 2 (SIK2) links lipid metabolism to survival of ovarian cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4111. doi:10.1158/1538-7445.AM2015-4111