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

Publisher: BioMed Central Country of Publication: England NLM ID: 100967800 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2407 (Electronic) Linking ISSN: 14712407 NLM ISO Abbreviation: BMC Cancer Subsets: MEDLINE

Original Publication: London : BioMed Central, [2001-

Drug Resistance, Neoplasm* ; Endoplasmic Reticulum Stress* ; Unfolded Protein Response*; Cisplatin/*pharmacology ; Exosomes/*metabolism ; Membrane Proteins/*metabolism ; Molecular Chaperones/*metabolism ; Nasopharyngeal Carcinoma/*drug therapy; Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Cell Proliferation ; Endoplasmic Reticulum Chaperone BiP ; Exosomes/genetics ; Humans ; Membrane Proteins/genetics ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Chaperones/genetics ; Nasopharyngeal Carcinoma/metabolism ; Nasopharyngeal Carcinoma/pathology ; Nasopharyngeal Neoplasms/drug therapy ; Nasopharyngeal Neoplasms/metabolism ; Nasopharyngeal Neoplasms/pathology ; Signal Transduction ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays

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.
(© 2021. The Author(s).)

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No. 81972554, No. 81672682 National Natural Science Foundation of China; No. 81702707 National Natural Science Foundation of China; No. BE2017680 Clinical Frontier Technology of Jiangsu; No. BK20201208 Natural Science Foundation of Jiangsu; No. Y-HS2017-074 CSCO Clinical Oncology Research Foundation of Beijing

Keywords: Chemoresistance; ER stress; ERp44; Exosomes; Nasopharyngeal carcinoma

0 (Antineoplastic Agents)
0 (ERP44 protein, human)
0 (Endoplasmic Reticulum Chaperone BiP)
0 (HSPA5 protein, human)
0 (Hspa5 protein, mouse)
0 (Membrane Proteins)
0 (Molecular Chaperones)
Q20Q21Q62J (Cisplatin)

Date Created: 20210908 Date Completed: 20211018 Latest Revision: 20211204

20250114

PMC8424889

10.1186/s12885-021-08712-9

34493236