MCOLN2 (Mucolipin-2) promotes autophagy to confer Adriamycin resistance in breast cancer by regulating mTOR degradation

Abstract Background Adriamycin is a cornerstone chemotherapeutic agent for advanced breast cancer, but its efficacy is frequently compromised by chemoresistance, a process in which macroautophagy is critically involved. However, the underlying mechanisms driving this autophagy-mediated resistance remain poorly understood. Methods Clinical data from patients with breast cancer who underwent chemotherapy were collected and the expression of MCOLN2 in tumor tissues was assessed. Using Adriamycin-resistant MCF-7/ADM cells and their parental MCF-7 cells, we investigated the role of MCOLN2 in regulating autophagic flux and mediating drug resistance. Key findings were further validated using an in vivo xenograft model. Results MCOLN2 expression was significantly upregulated in Adriamycin-resistant MCF-7/ADM cells and chemoresistant patient samples, where high levels correlated with poor prognosis. Knockdown of MCOLN2 sensitized MCF-7/ADM cells to Adriamycin both in vitro and in vivo, whereas its overexpression conferred resistance in parental MCF-7 cells. Mechanistically, MCOLN2 promoted autophagy, as evidenced by increased LC3-II levels and autophagosome formation. This pro-autophagic effect was mediated by MCOLN2-induced destabilization and lysosomal degradation of mTOR. Consequently, pharmacological or genetic inhibition of autophagy effectively reversed the MCOLN2-driven chemoresistance. Conclusion The MCOLN2-mTOR-autophagy axis has a critical role in the development of therapeutic resistance to Adriamycin in breast cancer. Targeting MCOLN2 could be a promising therapeutic strategy to overcome Adriamycin resistance in breast cancer patients.