Nox1 promotes colon cancer cell metastasis via activation of the ADAM17 pathway

H.-P. Wang, X. Wang, L.-F. Gong, W.-J. Chen, Z. Hao, S.-W. Feng, Y.-B. Wu, T. Ye, Y.-K. Cai

Department of General Surgery, Shanghai Fifth People Hospital Affiliated to Fudan University, Shanghai, China. yetao104@126.com

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• Oncology

OBJECTIVE: Reactive oxygen species (ROS) generated by endogenous metabolic enzymes are involved in a variety of pathology processes, including cancer. In particular, superoxide-generating NADPH oxidase 1 (Nox1), a member of Nox enzyme family, is highly expressed in the colon tissue and has been implicated in physiological and pathophysiological states of colon cancer. However, the underlying molecular mechanism of Nox1 in the regulation of colon cancer progression remains largely unknown.

MATERIALS AND METHODS: In vitro scratch wound healing and invasion assays were used to compare the migration and invasion abilities of HT29 cells in which Nox1 protein levels were manipulated. Western blot assay was performed to detect the expression of key proteins of the EGFR-PI3K-AKT signaling pathway. Immunoprecipitation assay was performed to detect the interaction between Nox1 and ADAM17.

RESULTS: Nox1 overexpression promoted colon cancer cell growth, migration, and invasion through the EGFR-PI3K-AKT signaling pathway. At the molecular level, Nox1 regulated the expression of tumor necrosis factor-α (TNF-α) converting enzyme (TACE)/a disintegrin and metalloprotease domain 17 (ADAM17). Furthermore, Nox1 interacted with and stabilized ADAM17 from ubiquitin-mediated degradation, leading to the activation of the ADAM17 signaling pathway.

CONCLUSIONS: This study suggests that Nox1 promotes colorectal cancer metastasis by modulating the stability of ADAM17.

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