title: Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma.
abstract: Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) - two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the in vitro findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells.
authors.affiliation: National Brain Research Centre, Department of Molecular and Cellular Neuroscience Division, Manesar, Gurgaon, Haryana 122051, India.
authors.forename: F
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: National Brain Research Centre, Department of Molecular and Cellular Neuroscience Division, Manesar, Gurgaon, Haryana 122051, India.
authors.forename: D
authors.initials: D
authors.lastname: Dixit
authors.affiliation: All India Institute of Medical Sciences, Department of Pathology, Ansari Nagar East, New Delhi 110029, India.
authors.forename: V
authors.initials: V
authors.lastname: Sharma
authors.affiliation: All India Institute of Medical Sciences, Department of Pathology, Ansari Nagar East, New Delhi 110029, India.
authors.forename: A
authors.initials: A
authors.lastname: Kumar
authors.affiliation: National Brain Research Centre, Department of Molecular and Cellular Neuroscience Division, Manesar, Gurgaon, Haryana 122051, India.
authors.forename: S D
authors.initials: SD
authors.lastname: Joshi
authors.affiliation: All India Institute of Medical Sciences, Department of Pathology, Ansari Nagar East, New Delhi 110029, India.
authors.forename: C
authors.initials: C
authors.lastname: Sarkar
authors.affiliation: National Brain Research Centre, Department of Molecular and Cellular Neuroscience Division, Manesar, Gurgaon, Haryana 122051, India.
authors.forename: E
authors.initials: E
authors.lastname: Sen
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000187:drug effects / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014174:Transketolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D007783:Lactones
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005954:Glucosephosphate Dehydrogenase; D006003:Glycogen; D006006:Glycogen Synthase; D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D019098:Telomerase; D014174:Transketolase; D016159:Tumor Suppressor Protein p53; C495635:NFE2L2 protein, human; C002602:costunolide; D007783:Lactones; C509186:TERT protein, human