Breast cancer resistance protein (BCRP/ABCG2), a xenobiotic efflux transporter, is responsible for anticancer resistance in tumors. NF-E2-related factor 2 (NRF2) is a critical transcription factor in cellular defense system by regulating the expression of antioxidant and detoxifying enzymes; however, its overexpression is often associated with tumor resistance to chemotherapy. In the present study, we demonstrate that NRF2 modulation affects the expression of hepatocyte growth factor receptor (HGFR/c-MET) and consequently suppresses BCRP/ABCG2 activity in cancer cells. Interfering RNA-mediated stable inhibition of NRF2 in both ovarian carcinoma SKOV3 and renal carcinoma A498 cell lines reduced the expression of c-MET and this was accompanied by BCRP/ABCG2 down-regulation. The treatment of cells with pharmacological or genetic inhibitor of c-MET decreased BCRP/ABCG2 level and subsequently increased intracellular accumulation of doxorubicin and Hoechst 33342, indicating a link between c-MET and BCRP/ABCG2 activity. As a potential molecular mechanism of altered c-MET expression, miR-206 was identified as a predictive regulator of c-MET. As experimental evidence, transient and stable expressions of miR-206 in SKOV3 and A498 cells repressed c-MET and BCRP/ABCG2 levels. In addition, NRF2-knockdown cancer cells expressed higher levels of miR-206 compared to the control cells, and the treatment of NRF2 knockdown cells with the miR-206 inhibitor could restore c-MET and BCRP/ABCG levels. Collectively, our results showed that the NRF2 silencing-mediated miR-206 regulation could suppress BCRP/ABCG2 levels through c-MET modulation, which is providing an additional evidence of chemosensitization of tumor cells by NRF2 inhibition.

Citation Format: Bo-hyun Choi, In-geun Ryoo, Donghyeok Kim, Sujin Lee, Mi-Kyoung Kwak. MiR-206-mediated c-MET suppression modulates BCRP/ABCG2 levels in NRF2-silenced cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 82. doi:10.1158/1538-7445.AM2017-82