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TGF-β-induced hCG-β regulates redox homeostasis in glioma cells

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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.

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Authors and Affiliations

  1. National Brain Research Centre, Manesar, 122 051, Haryana, India

    Fahim Ahmad, Sadashib Ghosh, Sanchari Sinha, Shanker Datt Joshi & Ellora Sen

  2. Paras Hospitals, Gurgaon, India

    Veer Singh Mehta

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  1. Fahim Ahmad
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  2. Sadashib Ghosh
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  3. Sanchari Sinha
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  4. Shanker Datt Joshi
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  5. Veer Singh Mehta
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  6. Ellora Sen
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Correspondence to Ellora Sen.

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11010_2014_2237_MOESM1_ESM.tif

ESM 1 ROS generation in glioma cells treated with TGF-β in the presence or absence of SB431542 as determined by DCFDA staining. Treatment with SB431542 increases ROS generation as determined by DCFDA staining. This is concurrent with the increased mitochondrial localization of ROS. Differential interference contrast (DIC) and immunofluorescence (DCFDA; 10 μM and Mitotracker Red; 100 nM) images showing ROS levels in U87MG glioma cells treated with TGF-β in the presence and absence of SB431542. Images were taken at 40x magnification. Scale bar is representative of 50 µm distance

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Ahmad, F., Ghosh, S., Sinha, S. et al. TGF-β-induced hCG-β regulates redox homeostasis in glioma cells. Mol Cell Biochem 399, 105–112 (2015). https://doi.org/10.1007/s11010-014-2237-6

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