STAT3 regulates 5‐Fu resistance in human colorectal cancer cells by promoting Mcl‐1–dependent cytoprotective autophagy

Chemoresistance to 5‐fluorouracil (5‐Fu)‐based chemotherapy is one of the primary reasons for the failure of colorectal cancer (CRC) management. STAT3 can mediate tumor drug resistance through a variety of diverse mechanisms. Nonetheless, the underlying mechanisms of STAT3‐induced 5‐Fu resistance in CRC are still poorly understood. Here, we aimed to investigate the potential mechanism(s) of STAT3‐induced 5‐Fu resistance in CRC. Quantitative RT‐PCR and Western blot were used to test the expression of STAT3 and Mcl‐1 in chemosensitive and chemoresistant CRC tissues and cell lines. After overexpression or knockdown of STAT3 or Mcl‐1, and/or treatment with or without 5‐Fu or chloroquine (CQ), we tested cell viability, inhibitory concentration 50% (IC50) value of 5‐FU, cell apoptosis, proliferation, migration, and autophagy. STAT3 and Mcl‐1 were significantly upregulated in the chemoresistant CRC tissues and cell lines, and STAT3 positively regulated Mcl‐1. Functional studies demonstrated that STAT3 promoted 5‐Fu resistance in CRC. Mechanistically, STAT3 triggered autophagy via Mcl‐1 to induce cancer chemoresistance. Our results show that STAT3 regulates 5‐Fu resistance in CRC by promoting Mcl‐1–dependent cytoprotective autophagy. Our results provide a novel role of STAT3 and may offer a new approach for managing CRC 5‐Fu resistance.

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