Inhibition of PRC1 elicits immunogenic cell death by triggering ROS-dependent ER stress in colorectal cancer via the Wnt/β-catenin signaling pathway.

Abstract

Due to the low response rate and severe side effects, the clinical efficacy of current immunotherapy for patients with colorectal cancer (CRC) remains unsatisfactory. Induction of immunogenic cell death (ICD) has been evidenced to be conducive to enhancing the survival benefit of immune checkpoint blockade (ICB) therapy. Protein regulator of cytokinesis 1 (PRC1) has been proven to be a tumor promoter in CRC and an immune marker. However, whether and how PRC1 is involved in the ICD regulation in CRC remains undiscovered. The current study identified the upregulation of PRC1 in CRC tissues and its prognostic value via bioinformatics analyses. Similarly, we determined the close correlation between PRC1 and ICD. In addition, knockdown of PRC1 induced ICD and downregulated PD-L1 expression in CRC cells, which was attenuated by ER stress inhibitor 4-PBA. PRC1 silencing elicited ER stress, but this effect was partially rescued by the ROS scavenger N-acetylcysteine. Mechanism investigation revealed that PRC1 could stimulate Wnt/β-catenin activation in CRC cells. According to results of rescue assays, activation of Wnt/β-catenin by BML-284 could partially reverse the effects of PRC1 knockdown on ER stress and ICD in CRC cells. Finally, the in vivo experiments demonstrated that silencing of PRC1 restrained tumor growth in CRC animal models. In conclusion, this study verified that inhibition of PRC1 expression could induce ICD in CRC by triggering ER stress via the Wnt/β-catenin signaling pathway. These findings highlight a novel molecular pathway whereby PRC1 exerts carcinogenic role in tumor immune microenvironment through ICD in CRC.