Synthesis and cellular effects of a mitochondria-targeted inhibitor of the two-pore potassium channel TASK-3

Pharmacol Res. 2021 Feb;164:105326. doi: 10.1016/j.phrs.2020.105326. Epub 2020 Dec 15.

Abstract

The two-pore potassium channel TASK-3 has been shown to localize to both the plasma membrane and the mitochondrial inner membrane. TASK-3 is highly expressed in melanoma and breast cancer cells and has been proposed to promote tumor formation. Here we investigated whether pharmacological modulation of TASK-3, and specifically of mitochondrial TASK-3 (mitoTASK-3), had any effect on cancer cell survival and mitochondrial physiology. A novel, mitochondriotropic version of the specific TASK-3 inhibitor IN-THPP has been synthesized by addition of a positively charged triphenylphosphonium moiety. While IN-THPP was unable to induce apoptosis, mitoIN-THPP decreased survival of breast cancer cells and efficiently killed melanoma lines, which we show to express mitoTASK-3. Cell death was accompanied by mitochondrial membrane depolarization and fragmentation of the mitochondrial network, suggesting a role of the channel in the maintenance of the correct function of this organelle. In accordance, cells treated with mitoIN-THPP became rapidly depleted of mitochondrial ATP which resulted in activation of the AMP-dependent kinase AMPK. Importantly, cell survival was not affected in mouse embryonic fibroblasts and the effect of mitoIN-THPP was less pronounced in human melanoma cells stably knocked down for TASK-3 expression, indicating a certain degree of selectivity of the drug both for pathological cells and for the channel. In addition, mitoIN-THPP inhibited cancer cell migration to a higher extent than IN-THPP in two melanoma cell lines. In summary, our results point to the importance of mitoTASK-3 for melanoma cell survival and migration.

Keywords: Antimycin A (PubChem CID: 16218979); FCCP (PubChem CID: 3330); Melanoma; Mitochondria; Pharmacological targeting; Staurosporin (PubChem CID: 44259); TASK-3 potassium channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / physiology
  • Potassium Channel Blockers / chemical synthesis
  • Potassium Channel Blockers / pharmacology*
  • Potassium Channels / metabolism*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacology*
  • Reactive Oxygen Species / metabolism

Substances

  • Potassium Channel Blockers
  • Potassium Channels
  • Pyrimidines
  • Reactive Oxygen Species
  • TASK3 protein, mouse
  • Adenosine Triphosphate