TRPM2 ION CHANNEL REGULATES CANCER CELL SURVIVAL IN A CALCIUM-DEPENDENT MANNER

Abstract

Since the late 1990s, TRPM2 ion channels have been broadly studied in various cancer types. The positive effect of TRPM2 expression on cancer cell viability has been associated with reduced cancer patient survival. However, the controversy about its function in cancer cells has remained unsolved. As such, the main objectives of this thesis are to 1) identify the involvement of TRPM2 dependent signaling pathways in cancer cell survival and death 2) investigate the role of TRPM2 in cancer cell migration and invasion 3) determine the importance of TRPM2-mediated calcium entry in mitochondrial integrity and function. Our results showed that TRPM2 functions as a calcium channel in gastric, breast and lung cancer cells and plays a promising role in regulating the intracellular calcium levels. The genetic silencing of TRPM2 inhibited cancer cell proliferation and promoted apoptosis. This inhibitory effect was due to a direct or indirect impact on mitochondrial integrity and function. The indirect effect of TRPM2 silencing on mitochondrial metabolism in gastric cancer cells was through autophagy regulation. Hence, TRPM2 silencing downregulated autophagy and led to the accumulation of oxidative stress which further caused mitochondrial dysfunction. Similarly, the direct effect of TRPM2 silencing on mitochondrial calcium uptake in breast cancer cells caused mitochondrial dysfunction and apoptosis. We also described an alternative mechanism in lung cancer cells, where TRPM2 depletion caused the intracellular accumulation of ROS and RNS and led to G2/M arrest and apoptosis. Furthermore, the tumor growth ability of cancer cells significantly reduced after TRPM2 depletion. In addition, we provided evidence that TRPM2 depleted cells lost their in vitro migration and invasion ability. In respect to the involved signaling pathways, we identified a JNK mediated-regulation of autophagy in gastric cancer cells, while AKT signaling was the major pathway modulated by TRPM2 in controlling cancer cell metastasis. Finally, we also highlighted the negative effect of TRPM2 expression on the response to chemotherapy drugs. Overall, our research findings provided convincing evidence on the therapeutic potential of TRPM2 in three important, invasive cancers which can be considered as a step towards a disease-free survival of cancer patients.