TRPM2 in Cancer. (June 2019)

• Record Type: Journal Article
• Authors: Miller, Barbara A.
• Is Part Of: Cell calcium. Volume 80(2019)
• Page Start: 8
• Page End: 17
• Publication Date: 2019-06
• Subjects: ACA N-(p-amylcinnamoyl)anthranilic acid -- ADPR adenosine diphosphate ribose -- cADPR cyclic adenosine diphosphate ribose -- 2-APB 2-aminoethoxydiphenyl borate -- ATGs autophagy-related proteins -- ATM ataxia-telangiectasia mutated serine/threonine protein kinase -- BECN1/Beclin-1 BECN1 gene encoding beclin-1 protein which plays a key role in autophagy -- BNIP3 BCL-2/adenovirus E1B 19 kDa protein-interacting protein 3 -- CAMKII calcium/calmodulin dependent protein kinase II -- COX4.1/4.2 cyclooxygenase 4.1/4.2 -- CREB cAMP responsive element-binding protein -- EGFR epidermal growth factor receptor -- FOXO3a Forkhead box O3 transcription factor -- GSH Glutathione -- HIF-1α hypoxia-inducible factor-1 –alpha -- HSP60 heat shock protein 60 -- Keap1 Ketch-like ECH-associated protein 1 -- IQGAP1 IQ motif containing GTPase activating protein 1 -- MCU Mitochondrial Calcium Uniporter -- NADH nicotinamide adenine dinucleotide -- NADPH nicotinamide adenine dinucleotide phosphate -- NOX NADPH oxidase -- Nrf2 nuclear factor (erythroid-derived 2)-related factor-2 -- PARG poly (ADPR) glycohydrolase -- PARP poly (ADPR) polymerase -- PIP2 phosphatidylinositol 4, 5-bisphosphate -- Pyk2 proline-rich tyrosine kinase 2 -- ROS reactive oxygen species -- Src proto-oncogene tyrosine-protein kinase -- TNF-α Tumor Necrosis Factor alpha -- Tom20 translocase of the outer mitochondrial membrane 20 -- TRPM Transient Receptor Potential Melastatin -- TRPM2-S Transient Receptor Potential Melastatin Channel 2- short isoform -- TRPM2-TE Transient Receptor Potential Melastatin Channel 2- tumor-enriched isoform -- VEGF Vascular Endothelial Growth Factor; TRPM2 -- HIF-1α -- CREB -- ROS -- Mitochondria -- Cancer; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2019.03.002
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: TRPM2 is highly expressed in many human cancers. It increases cell survival and inhibition reduces viability of malignant cells. TRPM2 inhibition impairs mitochondrial function, bioenergetics and autophagy. TRPM2 inhibition reduces antioxidant defenses and increases ROS levels. Targeting TRPM2 may be a novel therapeutics approach in treatment of many cancers. Abstract: The TRP ion channel TRPM2 has an essential function in cell survival and protects the viability of a number of cell types after oxidative stress. It is highly expressed in many cancers including breast, prostate, and pancreatic cancer, melanoma, leukemia, and neuroblastoma, suggesting it promotes cancer cell survival. TRPM2 is activated by production of ADP-ribose (ADPR) following oxidative stress, which binds to the C-terminus of TRPM2, resulting in channel opening. In a number of cancers including neuroblastoma, TRPM2 has been shown to preserve viability and mechanisms have been identified. Activation of TRPM2 results in expression of transcription factors and kinases important in cell proliferation and survival including HIF-1/2α, CREB, nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2), and Pyk2, and Src phosphorylation. Together, HIF-1/2α and CREB regulate expression of genes encoding proteins with roles in mitochondrial function including members of the electron transport complex involved in ATP production. These contribute to lower mitochondrial ROS production while expression of antioxidants regulated by HIF-1/2α, FOXO3a, CREB, and Nrf2 is maintained. CREB is also important in control of expression of key proteins involved in autophagy. When TRPM2-mediated calcium influx is inhibited, mitochondria are dysfunctional, cellular bioenergetics are reduced, production of ROS is increased, and autophagy and DNA repair are impaired, decreasing tumor growth and increasing chemotherapy sensitivity. Inhibition of TRPM2 expression or function results in decreased tumor proliferation and/or viability in many malignancies including breast, gastric, pancreatic, prostate, head and neck cancers, melanoma, neuroblastoma, and T-cell and acute myelogenous leukemia. However, in a small number of malignancies, activation of TRPM2 rather than inhibition has been reported to reduce tumor cell survival. Here, TRPM2-mediated Ca 2+ signaling and mechanisms of regulation of cancer cell growth and survival are reviewed and controversies discussed. Evidence suggests that targeting TRPM2 may be a novel therapeutic approach in many cancers.