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F-actin reorganization by V-ATPase inhibition in prostate cancer

Yamhilette Licon-Munoz1, Vera Michel1, Colleen A Fordyce1

  • 1Department of Biochemistry and Molecular Biology, School of Medicine, University of New Mexico, Albuquerque, New Mexico 87131, USA.

Biology Open
|October 18, 2017
PubMed

Insights

Inhibiting the vacuolar ATPase (V-ATPase) proton pump disrupts cellular pH balance and impairs prostate cancer cell migration. Novel F-actin rings form in response to V-ATPase inhibition, suggesting a cellular defense mechanism.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The vacuolar ATPase (V-ATP) proton pump is crucial for maintaining cellular pH homeostasis.
  • Its role and the cellular responses to its inhibition in cancer, particularly prostate cancer, are not fully understood.
  • Prostate cancer (PCa) cells, especially highly metastatic ones, exhibit unique cellular mechanisms.

Purpose of the Study:

  • To investigate the effects of V-ATPase inhibition on prostate cancer cell line PC-3.
  • To elucidate the cellular mechanisms underlying V-ATPase inhibition in metastatic PCa.
  • To understand the role of V-ATPase in regulating cellular pH, vesicle trafficking, and cytoskeleton dynamics.

Main Methods:

  • Utilized V-ATPase inhibitors to study their impact on PC-3 cells.
  • Assessed endo-lysosomal pH, vesicle trafficking, cell migration, and invasion.
  • Examined F-actin cytoskeleton organization, filopodial projections, and V-ATPase localization.
  • Investigated the pH-dependence of F-actin ring formation using chloroquine.

Main Results:

  • V-ATPase inhibition led to impaired endo-lysosomal pH, vesicle trafficking, migration, and invasion in PC-3 cells.
  • Accumulation of V-ATPase in the Golgi and recycling endosomes indicated impaired vesicle return to the plasma membrane.
  • V-ATPase inhibition caused significant F-actin cytoskeleton reorganization, reduced filopodia, and decreased migration velocity.
  • Novel pH-dependent F-actin rings formed in the cytoplasm upon extended V-ATPase inhibition.

Conclusions:

  • V-ATPase inhibition severely disrupts cellular processes in metastatic prostate cancer cells.
  • The formation of F-actin rings may represent a cellular attempt to compensate for widespread traffic defects induced by V-ATPase inhibition.
  • These findings highlight V-ATPase as a potential therapeutic target in prostate cancer.
Keywords:
Bafilomycin AConcanamycin AEndo-lysosomal pHF-actinProstate cancerVacuolar H+-ATPase proton pump

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