Deubiquitinating enzyme UCHL1 stabilizes CAV1 to inhibit ferroptosis and enhance docetaxel resistance in nasopharyngeal carcinoma.

Abstract

The overexpression of CAV1 in many cancers is linked to chemotherapy resistance, but the exact mechanisms by which CAV1 contributes to resistance in nasopharyngeal carcinoma (NPC) are not fully known. Our research aims to elucidate the potential pathways by which CAV1 contributes to chemotherapy resistance in NPC, providing a basis for developing strategies to overcome resistance. A docetaxel-resistant NPC cell line was established, and CAV1 expression was analyzed in the cell line and the resistant variant using western blot. The sensitivity of the resistant cell line to docetaxel was assessed via cell counting kit-8, colony formation assays, and flow cytometry. Flow cytometry was used to measure lipid reactive oxygen species levels, while kits were employed to determine Fe2+ and malondialdehyde concentrations. The Ubibrowser database helped identify ubiquitination enzymes that interact with CAV1. The binding relationship between UCHL1 and CAV1 was studied using co-immunoprecipitation and immunofluorescence, which also evaluated the deubiquitination activity of UCHL1 on CAV1. CAV1 is overexpressed in NPC tissues and cells, correlating with adverse patient prognoses. In docetaxel-resistant cells, CAV1 expression is elevated compared to standard NPC cells. Silencing CAV1 increased the sensitivity of these resistant cells to docetaxel. Additionally, treatment with the ferroptosis inducer erastin could counteract the effects of CAV1 overexpression on drug resistance. UCHL1 interacted with CAV1 and inhibited its ubiquitin-mediated degradation pathway. By deubiquitinating CAV1, UCHL1 stabilizes and increases its expression, which inhibits ferroptosis and enhances the resistance of NPC cells to docetaxel.