title: Oxidative stress activates the TRPM2-Ca2+-CaMKII-ROS signaling loop to induce cell death in cancer cells.
abstract: High intracellular levels of reactive oxygen species (ROS) cause oxidative stress that results in numerous pathologies, including cell death. Transient potential receptor melastatin-2 (TRPM2), a Ca2+-permeable cation channel, is mainly activated by intracellular adenosine diphosphate ribose (ADPR) in response to oxidative stress. Here we studied the role and mechanisms of TRPM2-mediated Ca2+influx on oxidative stress-induced cell death in cancer cells. We found that oxidative stress activated the TRPM2-Ca2+-CaMKII cascade to inhibit early autophagy induction, which ultimately led to cell death in TRPM2 expressing cancer cells. On the other hand, TRPM2 knockdown switched cells from cell death to autophagy for survival in response to oxidative stress. Moreover, we found that oxidative stress activated the TRPM2-CaMKII cascade to further induce intracellular ROS production, which led to mitochondria fragmentation and loss of mitochondrial membrane potential. In summary, our data demonstrated that oxidative stress activates the TRPM2-Ca2+-CaMKII-ROS signal loop to inhibit autophagy and induce cell death.
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China; Department of Molecular Medicine and Pathology, University of Auckland, New Zealand.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China. Electronic address: jianbyue@cityu.edu.hk.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Yue
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D018384:Oxidative Stress; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Autophagy; Ca(2+); CaMKII; Oxidative stress; Reactive oxygen species; TRPM2