Abstract 3020: The gep protooncogene Gα12 mediates LPA-stimulated activation of CREB in ovarian cancer cells.

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Abstract Lysophosphatidic acid (LPA), plays a critical role in the pathophysiology of ovarian cancers. Our previous studies have shown that LPA stimulates the proliferation of ovarian cancer cells through GNA12, the gep protooncogene Gα12. The present study is focused on identifying the Gα12-dependent mechanism through which LPA stimulates the proliferation of ovarian cancer cells. Using ovarian cancer cells in which the expression of Gα12 is silenced, we demonstrate here that Gα12-dependent mitogenic signaling by LPA involves the atypical activation of the transcription factor, cAMP-response element binding protein (CREB). Protein/DNA array analyses using LPA-stimulated Hey8 cells in which the expression of Gα12 was silenced indicated the potent but Gα12-dependent activation of CREB by LPA. After validating the array data with immunoblot analysis using antibodies specific to Ser133-phosphorylated active form of CREB, we demonstrate that the expression of the constitutively activated mutant of Gα12 stimulate the activation of CREB even in the absence of LPA whereas silencing of Gα12 abrogates such LPA-stimulated activation in multiple ovarian cancer cell lines. Furthermore, our results indicate that the robust activation of CREB by LPA is an early event, which can be monitored upon LPA stimulation from 3 minutes onwards. In addition, we establish that LPA/Gα12-dependent activation of CREB involves an atypical cAMP-independent mechanism involving Ras and ERK. More significantly, our findings indicate that the expression of the dominant negative mutant of CREB (S133A) leads to a reduction in LPA-stimulated increase in Cyclin A levels along with an attenuation of LPA-stimulated proliferation of these cells. Thus, these studies unravel a novel Gα12-dependent mechanism involving CREB through which LPA stimulates the proliferation of ovarian cancer cells. Citation Format: Ji Hee Ha, Danny Dhanasekaran, Jeremy Ward, Yoon Mi Yang, Sang Geon Kim, Lakshmi Varadarajalu. The gep protooncogene Gα12 mediates LPA-stimulated activation of CREB in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3020. doi:10.1158/1538-7445.AM2013-3020