TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase.
Loretta FerreraRaffaella BarbieriCristiana PiccoPaolo ZuccoliniAlessia RemiganteSara BertelliMaria Rita FumagalliGiovanni ZifarelliCaterina Anna Maria La PortaPaola GavazzoMichael PuschPublished in: International journal of molecular sciences (2021)
Tumor microenvironments are often characterized by an increase in oxidative stress levels. We studied the response to oxidative stimulation in human primary (IGR39) or metastatic (IGR37) cell lines obtained from the same patient, performing patch-clamp recordings, intracellular calcium ([Ca2+]i) imaging, and RT-qPCR gene expression analysis. In IGR39 cells, chloramine-T (Chl-T) activated large K+ currents (KROS) that were partially sensitive to tetraethylammonium (TEA). A large fraction of KROS was inhibited by paxilline-a specific inhibitor of large-conductance Ca2+-activated BK channels. The TEA-insensitive component was inhibited by senicapoc-a specific inhibitor of the Ca2+-activated KCa3.1 channel. Both BK and KCa3.1 activation were mediated by an increase in [Ca2+]i induced by Chl-T. Both KROS and [Ca2+]i increase were inhibited by ACA and clotrimazole-two different inhibitors of the calcium-permeable TRPM2 channel. Surprisingly, IGR37 cells did not exhibit current increase upon the application of Chl-T. Expression analysis confirmed that the genes encoding BK, KCa3.1, and TRPM2 are much more expressed in IGR39 than in IGR37. The potassium currents and [Ca2+]i increase observed in response to the oxidizing agent strongly suggest that these three molecular entities play a major role in the progression of melanoma. Pharmacological targeting of either of these ion channels could be a new strategy to reduce the metastatic potential of melanoma cells, and could complement classical radio- or chemotherapeutic treatments.
Keyphrases
- induced apoptosis
- oxidative stress
- genome wide identification
- protein kinase
- squamous cell carcinoma
- small cell lung cancer
- cell cycle arrest
- dna damage
- cell death
- reactive oxygen species
- gene expression
- mass spectrometry
- signaling pathway
- cell proliferation
- ischemia reperfusion injury
- risk assessment
- case report
- single molecule
- photodynamic therapy
- pi k akt
- visible light
- solid state