title: TGF-β-induced hCG-β regulates redox homeostasis in glioma cells.
abstract: Transforming growth factor (TGF-β) is associated with the progression of glioblastoma multiforme (GBM)-the most malignant of brain tumors. Since there is a structural homology between TGF-β and human chorionic gonadotropin (hCG) and as both TGF-β and hCG-β are known regulators of oxidative stress and survival responses in a variety of tumors, the role of TGF-β in the regulation of hCG-β and its consequences on redox modulation of glioblastoma cells was investigated. A heightened hCG-β level was observed in GBM tumors. TGF-β treatment increased hCG-β expression in glioma cell lines, and this heightened hCG-β was found to regulate redox homeostasis in TGF-β-treated glioma cells, as siRNA-mediated knockdown of hCG-β (i) elevated reactive oxygen species (ROS) generation, (ii) decreased thioredoxin Trx1 expression and thioredoxin reductase (TrxR) activity, and (iii) abrogated expression of TP53-induced glycolysis and apoptosis regulator (TIGAR). Silencing of hCG-β abrogated Smad2/3 levels, suggesting the existence of TGF-β-hCG-β cross-talk in glioma cells. siRNA-mediated inhibition of elevated TIGAR levels in TGF-β-treated glioma cells was accompanied by an increase in ROS levels. As a farnesyltransferase inhibitor, Manumycin is known to induce glioma cell apoptosis in a ROS-dependent manner, and we investigated whether Manumycin could induce apoptosis in TGF-β-treated cells with elevated hCG-β exhibiting ROS-scavenging property. Manumycin-induced apoptosis in TGF-β-treated cells was accompanied by elevated ROS levels and decreased expression of hCG-β, Trx1, Smad2/3, and TIGAR. These findings indicate the existence of a previously unknown TGF-β-hCG-β link that regulates redox homeostasis in glioma cells.
authors.affiliation: National Brain Research Centre, Manesar, 122 051, Haryana, India.
authors.forename: Fahim
authors.initials: F
authors.lastname: Ahmad
authors.forename: Sadashib
authors.initials: S
authors.lastname: Ghosh
authors.forename: Sanchari
authors.initials: S
authors.lastname: Sinha
authors.forename: Shanker Datt
authors.initials: SD
authors.lastname: Joshi
authors.forename: Veer Singh
authors.initials: VS
authors.lastname: Mehta
authors.forename: Ellora
authors.initials: E
authors.lastname: Sen
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000502:physiology*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D010084:Oxidation-Reduction; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D018997:Chorionic Gonadotropin, beta Subunit, Human; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; C054474:manumycin