SEC24C suppresses the propagation and chemoresistance of hepatocellular carcinoma by promoting unfolded protein response-related apoptosis.

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.

NDRG1 overcomes resistance to immunotherapy of pancreatic ductal adenocarcinoma through inhibiting ATG9A-dependent degradation of MHC-1.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is resistant to immune checkpoint blockade (ICB) therapies. Emerging evidence suggests that NDRG1 may be an important target for the development of new therapies for PDAC. Herein, we investigated the novel roles of NDRG1 and Combretastatin A-4 (CA-4) in the treatment of PDAC ICB resistance. METHODS: Enrichment of MHC class I was detected by RNA sequence and verified by RT-qPCR and immunoblotting in NDRG1-knockdown human pancreatic cancer cell lines. The protein degradation mode was found by stimulation with various inhibitors, and the autophagy degradation pathway was found by immunoprecipitation and immunolocalization. The roles of NDRG1 and MHC-I in immunotherapy were investigated by orthotopic solid tumors, histology, immunohistochemistry, multiplex immunofluorescence staining and flow cytometry. RESULTS: Here, we identified a previously undescribed role of NDRG1 in activating major histocompatibility complex class 1 (MHC-1) expression in pancreatic ductal adenocarcinoma (PDAC) cells through lysosomal-autophagy-dependent degradation. In mouse models of PDAC, either tumor cell overexpression or pharmacologic activation of NDRG1 leads to MHC-1 upregulation in tumor cells, which in turn promotes the infiltration and activity of CD8 + T cells, enhances anti-tumor immunity, and overcomes resistance to ICB therapy. Moreover, combination therapy of CA-4 and ICB overcomes the drug resistance of pancreatic cancer to ICB therapy. In PDAC patients, NDRG1 expression correlates with high MHC-1 expression and better survival. CONCLUSION: Our results reveal NDRG1 in PDAC cancer cells as a tumor suppressor and suggest that pharmaceutically targeting NDRG1 is a promising way to overcome pancreatic cancer resistance to immunotherapy and provides a potential therapeutic strategy for the treatment of pancreatic cancer patients.