Abstract LB-091: Hedgehog signaling induces drug resistance in gastric cancer cells via upregulation of ABCG2

Abstract

Abstract Gastric cancer is the third leading cause of cancer-related mortality worldwide. Currently, there are no specific therapeutic options to cure gastric cancer, and chemotherapy is frequently used. Some patients respond initially to chemotherapy but all patients eventually succumb to the disease. Thus, identifying molecular mechanisms responsible for chemotherapy resistance may help design novel strategies to sensitize cancer cells to chemotherapy. In this study, we revealed that treatment with chemotherapeutic reagents CDDP and 5Fu induced expression of GLI1, GLI2 and PTCH1 in gastric cancer cell lines, suggestive of hedgehog (Hh) signaling activation. GLI1 knockdown sensitized gastric cancer cells to CDDP and 5Fu treatment whereas ectopic GLI1 expression desensitized cancer cells to these treatments. Further analyses indicate elevated Hh signaling is associated with an increase in putative cancer stem cell marker expression, such as ABCG2. We found that GLI1 protein binds to the promoter of ABCG2 through a Gli-binding consensus site. Disruption of ABCG2 function, through ectopic expression of an ABCG2 dominant negative construct or a specific ABCG2 inhibitor, resulted in an increase of drug sensitivity both in culture and in mice. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high ABCG2 expression was associated with poor survival in the gastric cancer patients who underwent chemotherapy. Taken together, we have identified a molecular mechanism by which gastric cancer cells gain chemotherapy resistance. Citation Format: BEIQIN YU, DONGSHENG GU, XIAOLI ZHANG, BINGYA LIU, JINGWU XIE. Hedgehog signaling induces drug resistance in gastric cancer cells via upregulation of ABCG2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-091.