STAT3-dependent TXNDC17 expression mediates Taxol resistance through inducing autophagy in human colorectal cancer cells

• Resistance cell lines are established by continuous inducing plan of gradually increasing the concentration of Taxol.
• High levels of TXNDC17 and phospho-STAT3 are associated with autophagy and Taxol resistance in human colorectal cell lines.
• Downregulation of TXNDC17 via shRNA could resensitize the cells to Taxol.
• Transcription factor STAT3 directly binds to promoter region of TXNDC17 to execute regulation function.

Taxol (paclitaxel) is one of the taxane class of anticancer drugs as a first-line chemotherapeutic agent against many cancers including colorectal cancer, breast cancer, non-small cell lung cancer, ovarian cancer and so on. It is verified to induce cytotoxicity in a concentration and time-dependent manner. Numerous novel formulations of Taxol have been remanufactured for better therapeutic effect. Though Taxol works as a common anticancer drug for a long time in clinical practice, drug resistance is a major limitation of its long-term administration. In-depth research on drug resistance is still in progress and researchers have made some achievements, however, the mechanism or key molecule related to Taxol resistance in colorectal cancer still remains to be explored. In the present study, we observed that the high expression of TXNDC17 (thioredoxin domain containing 17) was associated with Taxol resistance in colorectal cancer cells. And TXNDC17 mediated Taxol resistance was related with increased basal autophagy level. Taxol exposure induced high levels of phospho-STAT3 (Tyr 705) and TXNDC17; and increase of basal autophagy in colorectal cancer cells. TXNDC17 overexpression cells obtained Taxol resistance and a high level of autophagy, and it is not surprising that stable downregulation of TXNDC17 accordingly reversed these phenomena. Interestingly, STAT3 could similarly work as TXNDC17 in spite of slighter effect compared to TXNDC17. And it has been proved that phospho-STAT3 (Tyr 705) possesses transcriptional regulation activity through forming dimmers. Many research revealed that transcription factor STAT3 affected more than 1000 gene products, and TXNDC17 is predicted to be a target gene of STAT3 at UCSC database. For the first time, we found STAT3 could bind promoter region of TXNDC17 (− 623 bp to − 58 bp relative to the transcription start site (TSS)) for regulating its expression. These results suggest the possibility that TXNDC17 could play an important role in Taxol resistance via enhancing autophagy in human colorectal cancer cells. TXNDC17 may become a potential target of colorectal cancer therapeutics.

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