α-MSH-PE38KDEL Kills Melanoma Cells via Modulating Erk1/2/MITF/TYR Signaling in an MC1R-Dependent Manner
Received 19 June 2020
Accepted for publication 9 November 2020
Published 3 December 2020 Volume 2020:13 Pages 12457—12469
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Leo Jen-Liang Su
Xilin Liu,1,* Hong Li,2,* Xianling Cong,3 Da Huo,1 Lele Cong,4 Guangzhi Wu1
1Department of Hand Surgery, China Japan Union Hospital of Jilin University, Changchun City, Jilin Province 130033, People’s Republic of China; 2Emergency Medical Department, China Japan Union Hospital of Jilin University, Changchun City, Jilin Province 130033, People’s Republic of China; 3Tissue Bank, China Japan Union Hospital of Jilin University, Changchun City, Jilin Province 130033, People’s Republic of China; 4Department of Dermatology, China Japan Union Hospital of Jilin University, Changchun City, Jilin Province 130033, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Guangzhi Wu
Department of Hand Surgery, China Japan Union Hospital of Jilin University, Changchun City, Jilin Province 130033, People’s Republic of China
Background/Objective: The immunotoxin α-MSH-PE38KDEL consisting of α-MSH and PE38KDEL showed high cytotoxicity on MSH receptor-positive melanoma cells, suggesting that α-MSH-PE38KDEL might be a potent drug for the treatment of melanoma. Herein, we explored whether the Erk1/2/MITF/TYR signaling, a verified target of α-MSH/MC1R, was involved in α-MSH-PE38KDEL-mediated cytotoxicity.
Methods: Human melanoma cell line A375, mouse melanoma cell line B16-F10, human breast cancer cell line MDA-MB-231 and human primary epidermal melanocytes (HEMa) with different expression levels of MC1R were used in this study. Cell apoptosis and viability were determined by using flow cytometry and MTT assays. Protein expressions were tested by Western blotting.
Results: The expression levels of MC1R in A375 and B16-F10 cells were significantly higher than that of MDA-MB-231 and HEMa. α-MSH-PE38KDEL treatment induced a significant inhibition in cell viability in A375 and B16-F10 cells, while showed no obvious influence in the viability of MDA-MB-231 and HEMa cells. However, knockdown of MC1R abolished α-MSH-PE38KDEL role in promoting cell apoptosis in A375 and B16-F10 cells, and upregulation of MC1R endowed α-MSH-PE38KDEL function to promote cell apoptosis in MDA-MB-231 and HEMa cells. Additionally, α-MSH-PE38KDEL treatment increased the phosphorylation levels of Erk1/2 and MITF (S73), and decreased MITF and TYR expressions in an MC1R-dependent manner. All of the treatments, including inhibition of Erk1/2 with PD98059, MC1R downregulation and MITF overexpression weakened the anti-tumor role of α-MSH-PE38KDEL in melanoma.
Conclusion: Collectively, this study indicates that α-MSH-PE38KDEL promotes melanoma cell apoptosis via modulating Erk1/2/MITF/TYR signaling in an MC1R-dependent manner.
Keywords: MC1R, melanoma, α-MSH-PE38KDEL, apoptosis, viability, Erk1/2/MITF/TYR
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