BioScience Trends. 2024;18(4):343-355. (DOI: 10.5582/bst.2024.01149)

SEC24C suppresses the propagation and chemoresistance of hepatocellular carcinoma by promoting unfolded protein responserelated apoptosis

Tao X, Wei H, Mao S, Wang J, Xue C, Yu W, Shi Y, Liu Y, Sun B

Cells routinely utilize the unfolded protein response (UPR) to alleviate endoplasmic reticulum (ER)- stress or trigger about apoptotic death under extreme ER-stress conditions. Tumor cells are subjected to persistent ER-stress due to their crowded microenvironment, but can maintain hyperactive proliferation under most stressful conditions. Therefore, understanding strategies employed by cancer cells to escape from UPR-related apoptosis has important medical implications. SEC24 homolog C (SEC24C) was found decreased in later colorectal cancer (CRC) stages, but its exact role in response to ER-stress and activation of UPR in hepatocellular carcinoma (HCC) remains to be elucidated. Here, we have identified the downregulation of SEC24C in human HCC sample and its suppressive role in regulating HCC proliferation and chemoresistance. Mechanistically, SEC24C was found to interact with eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3 or PERK) and activate the downstream UPR-related apoptosis. During this process, SEC24C was observed to be anchored in nucleus under normal condition but responded immediately to ER-stress and could subsequently translocate to the ER. Furthermore, overexpression of SEC24C significantly augmented the efficacy of bortezomib in HCC treatment. In conclusion, our findings revealed a novel role of SEC24C in regulating HCC proliferation and chemoresistance by modulating UPR activation.

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