Exosomal ERp44 derived from ER-stressed cells strengthens cisplatin resistance of nasopharyngeal carcinoma

Abstract

Background Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in head and neck. Platinum-based chemotherapy is an important treatment for NPC. However, the molecular mechanism of resistance to platinum drug remains unknown. Endoplasmic reticulum resident protein 44(ERp44), an unfolded protein response (UPR)-induced endoplasmic reticulum(ER) protein, is induced during ER stress. This research explored the mechanism of ERp44 in strengthening cisplatin resistance in NPC. Methods Western blot and immunohistochemistry were used to investigate the expression of ERp44 and Glucose-Regulated Protein 78(GRP78) in NPC. We took CCK8 to detect the role of ERp44 on cell chemosensitivity. Flow cytometric analysis and western blot were taken to analyze cell apoptosis. We performed differential centrifugation to isolate exosomes from serum or conditioned media of cells and analyzed the impact of exosomal ERp44 on cells cisplatin sensitivity. Finally, the results were confirmed in vivo. Results We found the increased expression of ERp44 and GRP78 in NPC and ERp44 was highly expressed in ER-stressed tissues. Cell proliferation was inhibited after cisplatin treatment when ERp44 was knocked down and ERp44 strengthened cisplatin resistance by influencing cell apoptosis and pyroptosis. Then we also collected exosomes and cell viability was increased after the addition of NPC-derived-exosomes with cisplatin treatment. More importantly, our results showed under ERS, NPC cells secreted exosomes containing ERp44 and could transfer them to adjacent cells to strengthen chemoresistance. Conclusion Our data suggested that exosomal ERp44 derived from ER-stressed NPC cells took an inevitable role in NPC chemoresistance and might act as a treatment target.

Construction and Validation of a UPR-Associated Gene Prognostic Model for Head and Neck Squamous Cell Carcinoma

“…It is becoming increasingly recognized that heterogeneity is significant in tumor progression and clinical decisions. The present evidence supports that chemotherapy resistance in cancers is linked to the UPR and ER stress [ 32 ]. One problem with the existing anticancer drugs is that a particular drug shows different sensitivities in different individuals.…”

“…ERP44 promotes progression in nasopharyngeal carcinoma via its interaction with ATP citrate lyase and regulation of epithelial-mesenchymal transition (EMT) [ 31 ]. Nasopharyngeal cancer cells release exosomes expressing ERP44, which may be delivered to adjacent cells to enhance chemoresistance under ER stress [ 32 ]. The above information suggests that ERP44 is an important gene influencing tumor progression and chemoresistance in HNSCC.…”

Relationship between miR-338-3p and Clinicopathological Parameters, Prognosis, and STAT3 mRNA Expression in Nasopharyngeal Carcinoma

“…The incidence rate is extremely high, which has seriously endangered human health. At present, it is considered that its pathogenesis is closely related to EB virus infection, chemical carcinogens, and genetic susceptibility genes [ 2 , 3 ]. Radiotherapy is still the main treatment for NPC, but the local recurrence and distant metastasis easily occur after radiotherapy, which limits its ability to further improve the survival rate of patients [ 4 ].…”

FT-IR Spectral Signature of Sensitive and Multidrug-Resistant Osteosarcoma Cell-Derived Extracellular Nanovesicles

“…EVs derived from the plasma of patients with acute myeloid leukemia (AML) confer idarubicin resistance in sensitive AML by inducing the expression of the drug efflux pumps MRD1 and MRP1 [ 36 ]. In stress conditions, nasopharyngeal carcinoma cells produced EVs containing the endoplasmic reticulum resident protein 44, which could be transferred to adjacent cells strengthening cisplatin resistance [ 37 ]. Additionally, a differential expression of exosomal circRNAs has been found in drug-resistant colon cancer cells compared to sensitive ones [ 38 ].…”