Thorium induced cytoproliferative effect in human liver cell HepG2: Role of insulin-like growth factor 1 receptor and downstream signaling

被引：20

作者：

Ali, Manjoor ^{[1
]}

Kumar, Amit ^{[1
]}

Pandey, Badri N. ^{[1
]}

机构：

[1] Bhabha Atom Res Ctr, Radiat Biol & Hlth Sci Div, Bombay 400085, Maharashtra, India

来源：

CHEMICO-BIOLOGICAL INTERACTIONS | 2014年 / 211卷

关键词：

Cytoproliferative effect; Thorium; IGF-1R; Akt and MAPK; Cyclin-E; MITOCHONDRIA; TOXICITY; TH-232;

D O I：

10.1016/j.cbi.2014.01.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Thorium-232 (Th-232), a naturally-occurring actinide has gained significant attention due to its immense potential as a nuclear fuel for advanced reactors. Understanding the biological effects of Th-232 would significantly impact its efficient utilization with adequate health protection. Humans administered with Th-232 (thorotrast patients) or experimental animal models showed that liver is one of the major sites of Th-232 accumulation. Present study reports cellular effects of Th-232-nitrate in a human-derived liver cell (HepG2). Results showed that the low concentration of Th-232 (0.1-10 I'M) induced proliferation of HepG2 cells which was inhibited by the pre-treatment of cells with neutralizing antibody against insulin-like growth factor I receptor (IGF-1R). Consistently, Th-232 treatment was found to increase the phosphorylated level of IGF-1R-associated molecule, IRSI which serves to activate PI3K and MAPK signaling pathways. Pre-treatment with specific inhibitors of PI3K (LY294002) or JNK-MAPK (SP600125) significantly abrogated the cytoproliferative effect of Th-232. Immunofluorescence analysis showed increased levels of phospho-Akt and phospho-p1K, downstream kinases of IGF-1R, in Th-232-treated HepG2 cells suggesting the role of IGF-IR-mediated signaling in Th-232-stimulated cell proliferation. The cell cycle analysis showed that Th-232 increased S and G2-M cell fractions concomitant to the increase of cyclin-E level. Thus, the present investigation highlights the role of IGF-IR-mediated signaling in the cytoproliferative effect of Th-232 in human liver cells at low concentration. (c) 2014 Elsevier Ireland Ltd. All rights reserved.

引用

页码：29 / 35

页数：7

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