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

Pharmacological research (2020-12-19)
Magdalena Bachmann, Andrea Rossa, Giuseppe Antoniazzi, Lucia Biasutto, Andrea Carrer, Monica Campagnaro, Luigi Leanza, Monika Gonczi, Laszlo Csernoch, Cristina Paradisi, Andrea Mattarei, Mario Zoratti, Ildiko Szabo
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
マイトマイシンC Streptomyces caespitosus由来, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
テトラメチルローダミンメチルエステルパークロレート, ≥95%