Attenuating glucose metabolism by Fbxw7 promotes Taxol sensitivity of colon cancer cells through downregulating NADPH oxidase 1 (Nox1)

Abstract

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 (Fbxw7) is a known tumor suppressor which is frequently downregulated in cancers. However, the biological roles and mechanisms of Fbxw7 in Taxol resistance are still under investigation.Methods: We report that Fbxw7 is significantly inactivated in CRC tumors and cell lines compared with normal tissues and colon cells. Expressions of Fbxw7 and Nox1 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 Fbxw7 and Nox1 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 Fbxw7 sensitized colon cancer cells to Taxol. Moreover, we observed a negative correlation between Fbxw7 and glucose metabolism. From the established Taxol-resistant (TR) cell line from HCT-116, Fbxw7 was found to be markedly downregulated in HCT-116 TR cells. We detected that NADPH oxidase 1 (Nox1), a superoxide-generating NADPH oxidase, is negatively regulated by Fbxw7. The Co-IP assay showed that Fbxw7 interacted with Nox1, which was observed to be significantly upregulated in CRC tissues. Nox1 therefore promotes the Taxol resistance and glucose metabolism of colon cancer cells.Finally, rescue experiments demonstrated that the Fbxw7-promoted Taxol sensitivity was partially through the Nox1-glycolysis axis. Restoration of Nox1 in Fbxw7-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 Fbxw7-Nox1-glucose metabolism axis could be an effective strategy against chemoresistant colon cancer.

The ubiquitin codes in cellular stress responses

“…Notably, the study showed that Hace2 directly targeted Rac1, but not NADPH oxidase. Another E3 ligase Fbxw7 can directly bind to and degrade NADPH oxidase 1 (Nox1) ( Wang et al 2021 ). RNF34 ablation was also reported to enhance the generation of NADPH oxidase-dependent ROS ( Fang et al 2021 ).…”

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

“…The inhibition or knockout of HDAC6 reduced glycolytic metabolism in triple-negative breast cancers [ 128 ]. The inhibition of 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3) enhanced the sensitivity of NSCLCs to erlotinib by decreasing autophagy [ 129 ], and inhibiting glycolysis was shown to overcome taxol-resistance in colorectal cancer cells [ 130 ]. These reports suggest that autophagy increases the expression of HDAC6, which in turn enhances glycolysis and anti-cancer drug resistance.…”

CDH17 as a Cell Surface Immunotherapy Target in Colorectal Cancer: An In Silico Analysis

“…• NOX1 promotes resistance to Taxol (a chemotherapeutic agent) in colon cancer cells, and such NOX1 tumorigenic effects can be overriden via glycolysis inhibition. In addition, NOX1 is negative regulated by the tumor suppressor FBXW7 in colon cancer [113].…”