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α-MSH-PE38KDEL Kills Melanoma Cells via Modulating Erk1/2/MITF/TYR Signaling in an MC1R-Dependent Manner

Xilin Liu1, Hong Li2, Xianling Cong3

  • 1Department of Hand Surgery, China Japan Union Hospital of Jilin University, Changchun City, Jilin Province 130033, People's Republic of China.

Oncotargets and Therapy
|December 10, 2020
PubMed
Abstract

Insights

The immunotoxin alpha-melanocyte-stimulating hormone-PE38KDEL (α-MSH-PE38KDEL) effectively targets melanoma cells by inducing apoptosis through the MC1R receptor. This targeted approach modulates the Erk1/2/MITF/TYR signaling pathway for melanoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • The immunotoxin α-MSH-PE38KDEL demonstrates significant cytotoxicity against melanoma cells expressing the MSH receptor.
  • The α-melanocyte-stimulating hormone (α-MSH) receptor (MC1R) is a key target for melanoma therapies.
  • The Erk1/2/MITF/TYR signaling pathway is a known target of α-MSH/MC1R.

Purpose of the Study:

  • To investigate the involvement of the Erk1/2/MITF/TYR signaling pathway in the cytotoxic effects of α-MSH-PE38KDEL on melanoma cells.
  • To determine the role of MC1R in mediating the anti-melanoma activity of α-MSH-PE38KDEL.

Main Methods:

  • Utilized human (A375) and mouse (B16-F10) melanoma cell lines, a human breast cancer line (MDA-MB-231), and human primary epidermal melanocytes (HEMa).
  • Assessed cell apoptosis and viability using flow cytometry and MTT assays.
  • Analyzed protein expression levels via Western blotting.

Main Results:

  • α-MSH-PE38KDEL significantly reduced viability in MC1R-high melanoma cells (A375, B16-F10) but not in MC1R-low cells (MDA-MB-231, HEMa).
  • MC1R knockdown abrogated α-MSH-PE38KDEL-induced apoptosis, while MC1R upregulation restored this effect in low-expressing cells.
  • Treatment increased Erk1/2 phosphorylation and decreased MITF/TYR expression in an MC1R-dependent manner, impacting melanoma cell apoptosis.

Conclusions:

  • α-MSH-PE38KDEL induces melanoma cell apoptosis through the MC1R receptor.
  • The cytotoxic mechanism involves the modulation of the Erk1/2/MITF/TYR signaling pathway.
  • These findings support α-MSH-PE38KDEL as a potential therapeutic agent for melanoma.
Keywords:
Erk1/2/MITF/TYRMC1Rapoptosismelanomaviabilityα-MSH-PE38KDEL

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