Abstract B26: The role of G alpha12 and thromboxane receptor beta interaction in bladder cancer progression

Abstract

Abstract In the United States, it is predicted that there will be over 70,000 new cases of bladder cancer this year. Bladder cancer is the fourth most common cancer in men and eighth in women. Our lab has previously identified Thromboxane receptor-β (TP-β) as potentially playing a role in bladder cancer progression. TP-β is a G-protein coupled receptor that is over-expressed in bladder cancer tumors and high levels of TP-β in bladder cancer patients correlate with decreased survival. G-proteins are involved in second messenger cascades that influence a variety of cellular functions, including transcription and motility. In multiple cellular systems TP-β has been found to interact with multiple G proteins such as Gαi, Gαs, Gα12, and Gα13. We found high levels of mRNA and protein expression of the G-protein, Gα12, in bladder cancer cell lines. We also observe high levels of Gα12 expression in human bladder cancer tissues. Studies using a constitutively active Gα12 mutant, suggest that signaling through Gα12 can contribute to oncogenic transformation. In this study we aim to elucidate the TP-β associated Gα12 dependent pathways that contribute to bladder cancer progression. We found that TP agonist U46619 increases cell migration and that treatment with TP antagonist blocks this increase in cell migration induced by U46619. TP agonist stimulation also increases the phosphorylation of extracellular regulated kinase (ERK) and U46619-induced phosphorylation of ERK is blocked with TP agonist treatment. Using a shRNA to knockdown Gα12 we observe a reduction in U46619-induced cell migration and ERK phosphorylation. Together our results suggest that TP-β mediated cell migration and the MAPK signaling pathway is in part regulated through Gα12. This work could have clinical implications by targeting the TP-β and Gα12 interaction as a potential therapeutic approach for bladder cancer treatment. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B26