Inhibition of ERO1L induces autophagy and apoptosis via endoplasmic reticulum stress in colorectal cancer.

Colorectal cancer (CRC) is one of the most common types of cancer with high incidence and mortality. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is overexpressed in CRC. This study aims to explore the role of ERO1L in CRC progression and evaluate the anti-tumor efficacy of the combination treatment of ERO1L inhibition with endoplasmic reticulum (ER) stress-inducing therapies. Herein, we found that ERO1L was elevated in CRC cell lines and patients. ER stress upregulated the expression of ERO1L, and ERO1L deficiency induced ER stress in CRC. ERO1L knockdown increased the susceptibility of CRC cells to ER stress. ERO1L contributed to the malignant phenotypes of CRC cells. Inhibition of ERO1L induced autophagy and caspase-dependent apoptosis by the induction of ER stress in CRC cells. Mechanically, the ERK1/2 pathway was involved in ERO1L knockdown-mediated apoptosis and autophagy. Combination treatment of ERO1L inhibition with ER stress-inducing agents, such as unfolded protein response (UPR)-targeting inhibitors and proteasome inhibitors, demonstrated enhanced anti-tumor capacity. In conclusion, ERO1L is overexpressed in CRC, and ERO1L deficiency induces apoptosis and autophagy via ER stress. ERO1L inhibition combined with ER stress-inducing therapies exhibits more effective anti-tumor activity against CRC. ERO1L may serve as a biomarker and therapeutic target for CRC treatment.