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

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

Research output: Contribution to journalArticle

50 Scopus citations

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 dehydrogenaseAand 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.

Original languageEnglish (US)
Pages (from-to)36284-36302
Number of pages19
JournalJournal of Biological Chemistry
Volume289
Issue number52
DOIs
StatePublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Chen, S. J., Hoffman, N. E., Shanmughapriy, S., Bao, L., Keefer, K., Conrad, K., Merali, S., Takahashi, Y., Abraham, T., Hirschler-Laszkiewicz, I., Wang, J. F., Zhang, X. Q., Song, J., Barrero, C., Shi, Y., Kawasawa, Y. I., Bayerl, M., Sun, T., Barbour, M., ... Miller, B. A. (2014). A splice variant of the human ion channel TRPM2 modulates neuroblastoma tumor growth through hypoxia-inducible factor (HIF)-1/2α. Journal of Biological Chemistry, 289(52), 36284-36302. https://doi.org/10.1074/jbc.M114.620922