Synthesis and cellular effects of a mitochondria-targeted inhibitor of the two-pore potassium channel TASK-3. (February 2021)

• Record Type: Journal Article
• Authors: Bachmann, Magdalena; Rossa, Andrea; Antoniazzi, Giuseppe; Biasutto, Lucia; Carrer, Andrea; Campagnaro, Monica; Leanza, Luigi; Gonczi, Monika; Csernoch, Laszlo; Paradisi, Cristina; Mattarei, Andrea; Zoratti, Mario; Szabo, Ildiko
• Is Part Of: Pharmacological research. Volume 164(2021)
• Publication Date: 2021-02
• Subjects: Staurosporin (PubChem CID: 44259) -- FCCP (PubChem CID: 3330) -- Antimycin A (PubChem CID: 16218979); Mitochondria -- TASK-3 potassium channel -- Pharmacological targeting -- Melanoma; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105326
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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.