Sensitization of colon cancer cells to cisplatin by Fbxw7 via negative regulation of the Nox1-mTOR pathway

Abstract

Colorectal cancer (CRC) is a human malignancy which associates with high mortality rate and poor prognosis. Despite the initial effectiveness in clinical applications of chemotherapeutic agents, a fraction of patients develops chemoresistance. Fbxw7 is an F-box protein serving as a substrate recognition subunit of E3 ubiquitin ligase, leading to degradation of various oncoproteins. In this study, Fbxw7 was significantly downregulated in CRC tumors as well as CRC cells. Fbxw7 suppressed CRC cell proliferation and migration. Moreover, we observed Fbxw7 was positively associated with cisplatin sensitivity. Fbxw7 was significantly downregulated in cisplatin resistant CRC cells. Overexpression of Fbxw7 effectively increased the cisplatin sensitivity of cisplatin resistant CRC cells. Co-immunoprecipitation and GST pull-down assays showed Fbxw7 bond with Nox1 which was a superoxide-generating NADPH oxidase and showed oncogenic roles in colon cancer cells. Interestingly, Fbxw7 downregulated Nox1 through binding it to degrade Nox1 protein. We demonstrated that Fbxw7 negatively regulated mTOR activity through downregulation of Nox1. Finally, overexpression of Fbxw7 effectively increased the cisplatin sensitivity of CRC cells. This process could be further overturned by Nox1 restoration in Fbxw7-overexpressing colon cancer cells. In summary, these results unveiled that Fbxw7 targeted Nox1 for degradation, resulting in blocking the downstream Nox1-mTORC1 signaling to sensitize CRC cells to cisplatin. Our study potentiates that targeting the Fbxw7-Nox1-mTOR pathway could be an effective approach to overcome chemoresistance of colon cancer cells.