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Tubulin-Targeted Therapy in Melanoma Increases the Cell Migration Potential by Activation of the Actomyosin

Marcin Luty1, Renata Szydlak1, Joanna Pabijan1

  • 1Institute of Nuclear Physics, Polish Academy of Sciences, Krakow PL-31342, Poland.

ACS Biomaterials Science & Engineering
|October 22, 2024
PubMed

Insights

Colchicine treatment paradoxically increases melanoma cell invasiveness by activating actomyosin, a pathway involving Rho-ROCK. Combination therapies can inhibit this compensatory effect, offering new therapeutic strategies for metastatic melanoma.

Area of Science:

  • Oncology
  • Cell Biology
  • Biophysics

Background:

  • Cancer metastasis is a leading cause of death, necessitating therapies that target both cancer cells and their spread.
  • Melanoma cell invasiveness varies, with less invasive (WM35) and more invasive (WM266-4) cell lines offering models to study metastatic mechanisms.

Purpose of the Study:

  • To investigate the effects of colchicine on melanoma cell actomyosin activation, proliferation, migration, and invasiveness.
  • To explore the biophysical mechanisms underlying colchicine's impact on cytoskeletal dynamics, particularly microtubules and actin filaments.
  • To evaluate the efficacy of combined therapies using Rho-associated protein kinase (ROCK) and myosin II inhibitors alongside colchicine.

Main Methods:

  • Utilized two melanoma cell lines (WM35, WM266-4) with varying invasiveness.
  • Applied confocal fluorescence microscopy to analyze cytoskeletal architecture.
  • Employed atomic force microscopy (AFM) and microconstriction channels to assess nanomechanical properties.
  • Investigated cellular responses to colchicine, Y-27632 (ROCK inhibitor), and (-)-blebbistatin (myosin II inhibitor).

Main Results:

  • Colchicine inhibited migration in most melanoma cells but paradoxically increased migration and invasiveness in a subpopulation.
  • Colchicine-induced increase in invasiveness was associated with stress fiber formation, compensating for microtubule disruption.
  • Simultaneous administration of ROCK and myosin II inhibitors counteracted colchicine's compensatory effects.
  • Colchicine treatment activated actomyosin, leading to increased cancer cell invasiveness via the Rho-ROCK pathway.

Conclusions:

  • Colchicine can enhance melanoma cell invasiveness through Rho-ROCK-dependent actomyosin activation, particularly in cells with disrupted microtubules.
  • Targeting the Rho-ROCK pathway offers a potential strategy to inhibit colchicine-induced invasiveness in melanoma.
  • Combined therapeutic approaches may overcome treatment resistance and reduce metastatic potential in melanoma.
Keywords:
actincolchicinecytoskeletoninvasivenessmelanomatubulin

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