TY - JOUR
T1 - α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth
AU - Sengupta, Soma
AU - Weeraratne, Shyamal Dilhan
AU - Sun, Hongyu
AU - Phallen, Jillian
AU - Rallapalli, Sundari K.
AU - Teider, Natalia
AU - Kosaras, Bela
AU - Amani, Vladimir
AU - Pierre-Francois, Jessica
AU - Tang, Yujie
AU - Nguyen, Brian
AU - Yu, Furong
AU - Schubert, Simone
AU - Balansay, Brianna
AU - Mathios, Dimitris
AU - Lechpammer, Mirna
AU - Archer, Tenley C.
AU - Tran, Phuoc
AU - Reimer, Richard J.
AU - Cook, James M.
AU - Lim, Michael
AU - Jensen, Frances E.
AU - Pomeroy, Scott L.
AU - Cho, Yoon Jae
N1 - Funding Information:
Acknowledgments The authors would like to acknowledge core facility support provided by the Boston Children’s Hospital, Broad Institute, Stanford Functional genomics Facility as well as support from the Stanford Cancer Center, Center for Children’s Brain Tumors at Stanford University, and the Child Health research Institute at lucile Packard Children’s Hospital. This work was funded by grants from the St. Baldrick’s Foundation Scholar Award and the Beirne Faculty Scholar endowment and (YJC); NIH grants U01CA176287 (YJC), r25NS070682 (SSg), r01CA109467 (SlP), P30 HD18655 (SlP).
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - GABRA5
KW - HOXA5
KW - MYC
KW - Medulloblastoma
KW - QHii066
UR - http://www.scopus.com/inward/record.url?scp=84896543307&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896543307&partnerID=8YFLogxK
U2 - 10.1007/s00401-013-1205-7
DO - 10.1007/s00401-013-1205-7
M3 - Article
C2 - 24196163
AN - SCOPUS:84896543307
SN - 0001-6322
VL - 127
SP - 593
EP - 603
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -