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Updated: Jan 31, 2026

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Notch signaling activation induces cell death in MAPKi-resistant melanoma cells

Dareen M Mikheil1,2,3, Kirthana Prabhakar2, Ayyan Arshad2

  • 1Comparative Biomedical Sciences Graduate Program, University of Wisconsin, Madison, Wisconsin.

Pigment Cell & Melanoma Research
|January 8, 2019
PubMed

Insights

Notch signaling impacts melanoma drug resistance. Activating Notch1 in resistant cells induces apoptosis, revealing a Notch-c-JUN-EDN1 pathway as a potential therapeutic target for melanoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • The role of Notch signaling in melanoma drug resistance remains unclear.
  • While NOTCH proteins are upregulated in metastatic melanoma, Notch inhibition doesn't affect sensitivity to MAPK inhibitors (MAPKi).

Purpose of the Study:

  • To investigate the role of Notch signaling in melanoma drug resistance.
  • To identify potential therapeutic targets within the Notch signaling pathway for MAPKi-resistant melanoma.

Main Methods:

  • Analysis of NOTCH1 expression in melanoma cell lines with varying MAPKi sensitivity.
  • Forced expression of NICD1 (active Notch1) in melanoma cells.
  • Whole transcriptome sequencing (RNA-Seq) to identify differentially regulated genes.
  • Gene knockdown experiments (EDN1, c-JUN).

Main Results:

  • NOTCH1 is downregulated in melanoma cells resistant to MAPKi.
  • Forced NICD1 expression induces apoptosis in MAPKi-resistant cells.
  • NICD1 differentially regulates endothelin 1 (EDN1) and c-JUN in MAPKi-sensitive versus resistant cells.
  • The Notch-c-JUN-EDN1 axis influences the survival of MAPKi-resistant melanoma cells.

Conclusions:

  • MAPKi-resistant melanoma cells become vulnerable to Notch signaling activation.
  • The Notch-c-JUN-EDN1 pathway represents a promising therapeutic target for overcoming MAPKi resistance in melanoma.
Keywords:
BRAFV600EEDN1Notchapoptosiscutaneous melanomadrug resistance

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