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: Fahim Ahmad, Sadashib Ghosh, Sanchari Sinha, Shanker Datt Joshi, Veer Singh Mehta, Ellora Sen
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 399 Issue 1-2 Pg. 105-12 (Jan 2015) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 25300619 (Publication Type: Journal Article)

Chemical References

• Chorionic Gonadotropin, beta Subunit, Human
• Polyenes
• Polyunsaturated Alkamides
• Reactive Oxygen Species
• Transforming Growth Factor beta
• manumycin

Topics

• Cell Line, Tumor
• Cell Survival
• Chorionic Gonadotropin, beta Subunit, Human (physiology)
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Glioblastoma (metabolism)
• Homeostasis
• Humans
• Oxidation-Reduction
• Polyenes (pharmacology)
• Polyunsaturated Alkamides (pharmacology)
• Reactive Oxygen Species (metabolism)
• Transforming Growth Factor beta (physiology)