STAT3 regulates 5-Fu resistance in human colorectal cancer cells by promoting Mcl-1-dependent cytoprotective autophagy.
Cancer science(2023)
Abstract
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% (IC ) 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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Key words
5-fluorouracil,Mcl-1,STAT3,colorectal cancer,cytoprotective autophagy
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