• Shekoufeh Almasi, Clara Yu Long, Andra Sterea, Derek Richard Clements, Shashi Gujar, and Yassine El Hiani.
• Departments of Biology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
• Cell. Physiol. Biochem. 2019 Jan 1; 52 (4): 742-757.

Background/AimsThe oxidative stress sensor transient receptor potential melastatin-2 (TRPM2) ion channel has recently gained attention in many types of cancer. The lung tissue is highly susceptible to oxidative stress-mediated injury and diseases; therefore, we aimed to determine whether TRPM2 plays an essential role in protecting lung cancer cells from oxidative damage while promoting cancer cell survival and metastasis.MethodsWe used two non-small cell lung (NSCLC) cell lines A549 and H1299 as a lung cancer model. We investigated the functional expression of TRPM2 using electrophysiology, qRT-PCR and Western blots. CFSE and flow cytometry were used to study TRPM2 role in proliferation, cell cycle and apoptosis. Gap closure chambers and Three-Tiered Chemotaxis Chamber were used to study the role of TRPM2 in metastasis. SCID mice were used to study the role of TRPM2 in lung tumor growth and metastasis.Resultswe demonstrate that TRPM2 is functionally expressed in NSCLC cells and that its downregulation significantly inhibits cell proliferation and promotes apoptosis. These results were concomitant with an induction in DNA damage and G2/M cell cycle arrest. TRPM2 silencing inhibits also lung cancer cells invasion ability and alters EMT processes. Mechanistically, TRPM2 downregulation causes an increase in the intracellular levels of reactive oxygen (ROS) and nitrogen (RNS) species, which in turn causes DNA damage and JNK activation leading to G2/M arrest, and an ultimate cell death. Finally, TRPM2 downregulation suppresses the growth of human lung tumour xenograft in SCID mice and TRPM2 depleted tumours exhibited a significant reduction in the mRNA expression level of EMT markers compared to the control tumors.ConclusionOur data provide new insights on the functional expression of TRPM2 in lung cancer, its essential role in tumour growth and metastasis through the control of JNK signaling pathway, and that TRPM2 could be exploited for targeted lung cancer therapies.© Copyright by the Author(s). Published by Cell Physiol Biochem Press.

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