| dc.description.abstract | Tumor cells face various microenvironmental stresses, such as oxidative stress and deprivation of oxygen and nutrients, which could disrupt protein homeostasis and induce endoplasmic reticulum (ER) stress. To survive, tumor cells must activate adaptive pathways, including the upregulation of unfolded protein response (UPR) observed in many solid tumors, which helps resolve stress and promote survival. While UPR activation aids tumor cells in the recovery of mild or moderate ER stress, severe or prolonged ER stress can instead trigger programmed cell death, e.g. apoptosis or paraptosis. In tumor cells, ER stress-induced paraptosis is regarded as a form of immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) and cytokines that stimulate anti-tumor immunity. Inducing ICD by surpassing tumor cells’ ER stress threshold emerges as a promising cancer treatment strategy. Selenium (Se) has been shown to induce ER stress and apoptosis in many cancer types without harming non-cancerous cells, rendering selenium-containing compounds potential chemotherapeutic agents. However, the differential impacts of Se on cancer versus non-cancerous cells, and the role of Se-mediated ER stress in ICD induction, remain poorly understood.
In this study, we investigated the effects of L-selenocystine (SeC) on colorectal cancer (CRC) cells compared to non-CRC cells. Our findings demonstrated that SeC treatment activated the IRE1 pathway and induced ER stress-mediated apoptosis in CRC cells, but not non-CRC cells. IRE1 knockdown exacerbated SeC-induced cell death in CRC cells, suggesting alternative pathways contributing to cell death under severe ER stress. SeC inhibited proteasome activity via ROS-mediated mechanisms in CRC cells, leading to polyubiquitinated protein accumulation. Moreover, SeC promoted the release of ICD factors, altered ER morphology, and induced extensive cytoplasmic vacuolization, indicating disruption of protein homeostasis and induction of paraptosis, which could enhance anti-tumor immune responses. Elevated selenium contents within the ER-derived vesicles and ER-localized ROS in SeC-treated CRC cells implied direct ER perturbation by SeC. Our findings provide insights into the molecular mechanisms underlying the selective anti-cancer effects of SeC, offering prospects for its precise application in cancer therapy. | en_US |