Referenced in: none

Automatically associated channels: TRP , TRPM , TRPM2

Title: A splice variant of the human ion channel TRPM2 modulates neuroblastoma tumor growth through hypoxia-inducible factor (HIF)-1/2α.

Authors: Shu-jen Chen, Nicholas E Hoffman, Santhanam Shanmughapriya, Lei Bao, Kerry Keefer, Kathleen Conrad, Salim Merali, Yoshinori Takahashi, Thomas Abraham, Iwona Hirschler-Laszkiewicz, Jufang Wang, Xue-Qian Zhang, Jianliang Song, Carlos Barrero, Yuguang Shi, Yuka Imamura Kawasawa, Michael Bayerl, Tianyu Sun, Mustafa Barbour, Hong-Gang Wang, Muniswamy Madesh, Joseph Y Cheung, Barbara A Miller

Journal, date & volume: J. Biol. Chem., 2014 Dec 26 , 289, 36284-302

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25391657

Abstract
The calcium-permeable ion channel TRPM2 is highly expressed in a number of cancers. In neuroblastoma, full-length TRPM2 (TRPM2-L) protected cells from moderate oxidative stress through increased levels of forkhead box transcription factor 3a (FOXO3a) and superoxide dismutase 2. Cells expressing the dominant negative short isoform (TRPM2-S) had reduced FOXO3a and superoxide dismutase 2 levels, reduced calcium influx in response to oxidative stress, and enhanced reactive oxygen species, leading to decreased cell viability. Here, in xenografts generated with SH-SY5Y neuroblastoma cells stably expressing TRPM2 isoforms, growth of tumors expressing TRPM2-S was significantly reduced compared with tumors expressing TRPM2-L. Expression of hypoxia-inducible factor (HIF)-1/2α was significantly reduced in TRPM2-S-expressing tumor cells as was expression of target proteins regulated by HIF-1/2α including those involved in glycolysis (lactate dehydrogenase A and enolase 2), oxidant stress (FOXO3a), angiogenesis (VEGF), mitophagy and mitochondrial function (BNIP3 and NDUFA4L2), and mitochondrial electron transport chain activity (cytochrome oxidase 4.1/4.2 in complex IV). The reduction in HIF-1/2α was mediated through both significantly reduced HIF-1/2α mRNA levels and increased levels of von Hippel-Lindau E3 ligase in TRPM2-S-expressing cells. Inhibition of TRPM2-L by pretreatment with clotrimazole or expression of TRPM2-S significantly increased sensitivity of cells to doxorubicin. Reduced survival of TRPM2-S-expressing cells after doxorubicin treatment was rescued by gain of HIF-1 or -2α function. These data suggest that TRPM2 activity is important for tumor growth and for cell viability and survival following doxorubicin treatment and that interference with TRPM2-L function may be a novel approach to reduce tumor growth through modulation of HIF-1/2α, mitochondrial function, and mitophagy.