FXR and Nrf2 Mediate the Effect of Carbon Ion Irradiation on Drug Transporter OATP1A2 in Cancer Cells

Organic anion transporting polypeptides (OATPs, gene symbol SLCO) are recognized as key factors in the absorption, distribution, and excretion of a wide range of endogenous and xenobiotic compounds, including many anti-neoplastic drugs. Several OATPs, such as OATP1A2, OATP1B1, and OATP1B3, have been found to be expressed in tumor cells and/or tissues, making them potential therapeutic targets for chemotherapy. Previous studies in our laboratory demonstrated that both X-ray and carbon ion irradiation induced the expression of OATP1A2 in the breast cancer cell line MCF7, resulting in enhanced killing effects of methotrexate, 5-fluorouracil, and paclitaxel following irradiation. In the present study, we evaluated the effect of carbon ions on the expression of OATP1A2, OATP1B1, and OATP1B3 in different cell lines (HCT116, HepG2, A549, and MCF7). It was found that only HepG2 and MCF7 cells exhibited an upregulation of OATP1A2 after irradiation. Mechanistically, carbon ions induced the expression of FXR and Nrf2, both of which specifically bind to the upstream regulatory sequence of SLCO1A2, the encoding gene for OATP1A2. Modulators of these transcription factors altered the induction of OATP1A2 following irradiation. Additionally, combined treatment of these modulators, methotrexate, and carbon ion irradiation resulted in a more significant killing effect on these cancer cells.