CD13 induces autophagy promoting hepatocellular carcinoma cells chemoresistance through P38/Hsp27/CREB/ATG7 pathway.

Chemoresistance of hepatocellular carcinoma is one of the most serious problems, which directly hinders the effect of chemotherapy agents. We previously reported that CD13 inhibition can enhance the cytotoxic efficacy of chemotherapy agents. In the present study, we utilizes liver cancer cell to explore molecular mechanism accounting for the relationship of CD13 and chemoresistance. We demonstrate that CD13 over-expression activates the P38/Hsp27/CREB signaling pathway to limit the efficacy of cytotoxic agents. Moreover, blockade of P38 or CREB sensitizes HCC cells to 5FU. Then, we discover that CREB binds onto ATG7 promoter to induce autophagy thereby promotes HCC cells chemoresistance. CD13 inhibition also down-regulated the expression of ATG7, autophagy, and the growth of tumor cells in vivo. Overall, combination CD13 inhibitor and chemotherpay agents may be a potential therapeutic strategy for overcoming drug resistance in HCC. SIGNIFICANCE STATEMENT: Our study demonstrates that CD13 promotes HCC cells chemoresistance via P38/Hsp27/CREB pathway. CREB regulates ATG7 transcription and expression to induce autophagy. Collectively, these results suggest that CD13 might serve as a potential target for overcoming HCC resistance.