α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth

Soma Sengupta, Shyamal Dilhan Weeraratne, Hongyu Sun, Jillian Phallen, Sundari K. Rallapalli, Natalia Teider, Bela Kosaras, Vladimir Amani, Jessica Pierre-Francois, Yujie Tang, Brian Nguyen, Furong Yu, Simone Schubert, Brianna Balansay, Dimitris Mathios, Mirna Lechpammer, Tenley C. Archer, Phuoc Tran, Richard J. Reimer, James M. Cook & 4 others Michael Lim, Frances E. Jensen, Scott L. Pomeroy, Yoon-Jae Cho

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Neural tumors often express neurotransmitter receptors as markers of their developmental lineage. Although these receptors have been well characterized in electrophysiological, developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors and, importantly, the effect of their targeting in brain cancers remains obscure. Here, we demonstrate high levels of GABRA5, which encodes the α5-subunit of the GABAA receptor complex, in aggressive MYC-driven, "Group 3" medulloblastomas. We hypothesized that modulation of α5-GABAA receptors alters medulloblastoma cell survival and monitored biological and electrophysiological responses of GABRA5-expressing medulloblastoma cells upon pharmacological targeting of the GABAA receptor. While antagonists, inverse agonists and non-specific positive allosteric modulators had limited effects on medulloblastoma cells, a highly specific and potent α5-GABAA receptor agonist, QHii066, resulted in marked membrane depolarization and a significant decrease in cell survival. This effect was GABRA5 dependent and mediated through the induction of apoptosis as well as accumulation of cells in S and G2 phases of the cell cycle. Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOXA5 target gene expression. siRNA-mediated knockdown of HOXA5 markedly blunted the response of medulloblastoma cells to QHii066. Furthermore, QHii066 sensitized GABRA5 positive medulloblastoma cells to radiation and chemotherapy consistent with the role of HOXA5 in directly regulating p53 expression and inducing apoptosis. Thus, our results provide novel insights into the synthetic lethal nature of α5-GABAA receptor activation in MYC-driven/Group 3 medulloblastomas and propose its targeting as a novel strategy for the management of this highly aggressive tumor.

Original languageEnglish (US)
Pages (from-to)593-603
Number of pages11
JournalActa Neuropathologica
Volume127
Issue number4
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Medulloblastoma
GABA-A Receptors
Growth
Brain Neoplasms
Cell Survival
Pharmacology
Apoptosis
GABA-A Receptor Agonists
Neurotransmitter Receptor
G2 Phase
S Phase
Small Interfering RNA
Neoplasms
Cell Cycle
Maintenance
Radiation
Gene Expression
Drug Therapy
Membranes

Keywords

  • GABRA5
  • HOXA5
  • Medulloblastoma
  • MYC
  • QHii066

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Sengupta, S., Weeraratne, S. D., Sun, H., Phallen, J., Rallapalli, S. K., Teider, N., ... Cho, Y-J. (2014). α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth. Acta Neuropathologica, 127(4), 593-603. https://doi.org/10.1007/s00401-013-1205-7

α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth. / Sengupta, Soma; Weeraratne, Shyamal Dilhan; Sun, Hongyu; Phallen, Jillian; Rallapalli, Sundari K.; Teider, Natalia; Kosaras, Bela; Amani, Vladimir; Pierre-Francois, Jessica; Tang, Yujie; Nguyen, Brian; Yu, Furong; Schubert, Simone; Balansay, Brianna; Mathios, Dimitris; Lechpammer, Mirna; Archer, Tenley C.; Tran, Phuoc; Reimer, Richard J.; Cook, James M.; Lim, Michael; Jensen, Frances E.; Pomeroy, Scott L.; Cho, Yoon-Jae.

In: Acta Neuropathologica, Vol. 127, No. 4, 01.01.2014, p. 593-603.

Research output: Contribution to journalArticle

Sengupta, S, Weeraratne, SD, Sun, H, Phallen, J, Rallapalli, SK, Teider, N, Kosaras, B, Amani, V, Pierre-Francois, J, Tang, Y, Nguyen, B, Yu, F, Schubert, S, Balansay, B, Mathios, D, Lechpammer, M, Archer, TC, Tran, P, Reimer, RJ, Cook, JM, Lim, M, Jensen, FE, Pomeroy, SL & Cho, Y-J 2014, 'α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth', Acta Neuropathologica, vol. 127, no. 4, pp. 593-603. https://doi.org/10.1007/s00401-013-1205-7
Sengupta S, Weeraratne SD, Sun H, Phallen J, Rallapalli SK, Teider N et al. α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth. Acta Neuropathologica. 2014 Jan 1;127(4):593-603. https://doi.org/10.1007/s00401-013-1205-7
Sengupta, Soma ; Weeraratne, Shyamal Dilhan ; Sun, Hongyu ; Phallen, Jillian ; Rallapalli, Sundari K. ; Teider, Natalia ; Kosaras, Bela ; Amani, Vladimir ; Pierre-Francois, Jessica ; Tang, Yujie ; Nguyen, Brian ; Yu, Furong ; Schubert, Simone ; Balansay, Brianna ; Mathios, Dimitris ; Lechpammer, Mirna ; Archer, Tenley C. ; Tran, Phuoc ; Reimer, Richard J. ; Cook, James M. ; Lim, Michael ; Jensen, Frances E. ; Pomeroy, Scott L. ; Cho, Yoon-Jae. / α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth. In: Acta Neuropathologica. 2014 ; Vol. 127, No. 4. pp. 593-603.
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