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Updated: May 10, 2026

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
07:41

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis

Published on: March 8, 2022

Suppression of antifolate resistance by targeting the myosin Va trafficking pathway in melanoma

María Piedad Fernández-Pérez1, María F Montenegro, Magalí Sáez-Ayala

  • 1Department of Biochemistry and Molecular Biology A, School of Biology, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, Murcia, Spain.

Neoplasia (New York, N.Y.)
|July 2, 2013
PubMed

Insights

Melanoma cells export drugs like methotrexate (MTX) via a novel pathway involving Akt2 and myosin Va, leading to drug resistance. Blocking this export reactivates cell death pathways, offering new therapeutic strategies for melanoma.

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Human melanoma frequently develops drug resistance, leading to poor patient outcomes.
  • Melanoma-specific mechanisms like melanosomal sequestration and drug exportation contribute to multidrug resistance.
  • The precise cellular processes underlying methotrexate (MTX) sequestration and exportation in melanoma remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which MTX is trapped in melanosomes and exported from melanoma cells.
  • To identify key mediators involved in MTX-induced melanosome trafficking and drug resistance.
  • To explore therapeutic strategies for overcoming MTX resistance in melanoma.

Main Methods:

  • Investigated the role of myosin Va (MyoVa) in MTX transport and melanosome exportation.
  • Examined the involvement of Akt2 signaling in MyoVa phosphorylation and melanosome trafficking.
  • Assessed the impact of MTX on protein phosphatase 2A activity.
  • Evaluated the efficacy of combination therapies aimed at blocking MTX exportation.

Main Results:

  • MTX treatment induces Akt2-dependent phosphorylation of MyoVa, enhancing its interaction with melanosomes and accelerating their export.
  • MTX affects melanosome trafficking and melanogenesis.
  • Blocking MTX exportation reactivates the E2F1 apoptotic pathway, involving p73 and apoptosis protease-activating factor 1.
  • The study identified a novel Akt2/MyoVa-mediated trafficking pathway contributing to melanoma drug resistance.

Conclusions:

  • A novel Akt2/MyoVa pathway mediates melanosome trafficking and promotes MTX resistance in melanoma.
  • Inhibition of this pathway restores sensitivity to MTX by enabling apoptosis.
  • Targeting this pathway presents a promising strategy for combination therapies to improve melanoma treatment outcomes.

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