Attenuating glucose metabolism by promotes Taxol sensitivity of colon cancer cells through downregulating oxidase 1 ().

Background: Colorectal cancer (CRC), one of the most common malignancies worldwide, is associated with poor survival and has a high mortality rate. Taxol is a chemotherapeutic agent that has been clinically applied as a first-line drug against diverse cancers. Yet, development of drug resistance has become the major challenge for anti-cancer treatments. F-box and WD40 domain protein 7 () is a known tumor suppressor which is frequently downregulated in cancers. However, the biological roles and mechanisms of in Taxol resistance are still under investigation.

Methods: We report that is significantly inactivated in CRC tumors and cell lines compared with normal tissues and colon cells. Expressions of and were detected from human colon tumors and cells by qRT-PCR and Western blot. Glycolysis rate was assessed by glucose uptake and lactate product assay. Interactions between and were determined by co-immunoprecipitation (Co-IP). Chemosensitivity and resistance of colon cancer cells were determined by MTT assay and Annexin V-FITC assay.

Results: Overexpression of sensitized colon cancer cells to Taxol. Moreover, we observed a negative correlation between and glucose metabolism. From the established Taxol-resistant (TR) cell line from HCT-116, was found to be markedly downregulated in HCT-116 TR cells. We detected that NADPH oxidase 1 (), a superoxide-generating NADPH oxidase, is negatively regulated by . The Co-IP assay showed that interacted with , which was observed to be significantly upregulated in CRC tissues. therefore promotes the Taxol resistance and glucose metabolism of colon cancer cells. Finally, rescue experiments demonstrated that the -promoted Taxol sensitivity was partially through the -glycolysis axis. Restoration of in -overexpressed TR colon cancer cells significantly recovered the Taxol resistance, which could be further overridden by glycolysis inhibition.

Conclusions: Collectively, this study uncovered that targeting the --glucose metabolism axis could be an effective strategy against chemoresistant colon cancer.