TRPM2 in Cancer

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 Ca²⁺ 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.

Keywords: CREB; Cancer; HIF-1α; Mitochondria; ROS; TRPM2.

Figure 1.. TRPM2 promotes growth of neuroblastoma xenografts and reduces ROS.

A. Athymic mice were injected in the flank with parental SH-SY5Y cells (Wild type, Wt), cells in which TRPM2 was deleted with CRISPR (two clones, KO-1, KO-2), or scrambled control cells (Scr-1, Scr-2). Representative photographs of tumors removed at 6 weeks after cell injection are shown. In two experiments (n=13–14), p≤0.01 for differences in Scr vs KO tumor volumes and weights. B. ROS levels were measured in SH-SY5Y neuroblastoma cells in which TRPM2 was depleted with CRISPR (two clones, KO-1, KO-2), or scrambled control cells (Scr-1, Scr-2). Cells were loaded with MitoSOX Red and intensity of fluorescence measured with confocal microscopy at baseline or 24 hours after treatment with 0.3 μM doxorubicin. A representative field of cells from each group and statistical analysis from a representative experiment are shown. Mitochondrial ROS were increased in TRPM2 depleted cells at baseline and after doxorubicin treatment. *p<0.05.

Figure 2.. TRPM2 Maintains Cell Survival through Modulation of HIF-1/2α, CREB, Nrf2, and Pyk2.

TRPM2 mediates expression of HIF-1/2α, CREB, and Nrf2 in neuroblastoma cells. Pyk2 phosphorylation and activation by TRPM2 through a Ca²⁺-dependent process is involved in modulating CREB expression. These factors contribute to maintenance of mitochondrial function and ATP production, and lower ROS levels through reduced ROS production and preservation of the antioxidant response. When TRPM2 is inhibited or depleted, Ca²⁺ influx into the cell and into mitochondria through the mitochondrial calcium uniporter (MCU) is reduced, expression of key transcription factors HIF-1/2α, CREB, and Nrf2 is decreased, mitochondrial function, cellular bioenergetics, and autophagy/mitophagy are impaired, activation of kinases including Pyk2 and Src and cell viability are reduced, and ROS levels and sensitivity to chemotherapy are increased.