کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2580422 | 1561630 | 2014 | 7 صفحه PDF | دانلود رایگان |
• Thorium (⩽10 μM) induced liver cell proliferation through IGF-1 receptor signaling.
• Thorium induced phosphorylation of IGF-1R substrate, IRS1.
• Akt and JNK-MAPK were found to mediate upstream events of IGF-1R activation.
Thorium-232 (232Th), 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 232Th would significantly impact its efficient utilization with adequate health protection. Humans administered with 232Th (thorotrast patients) or experimental animal models showed that liver is one of the major sites of 232Th accumulation. Present study reports cellular effects of 232Th-nitrate in a human-derived liver cell (HepG2). Results showed that the low concentration of 232Th (0.1–10 μM) induced proliferation of HepG2 cells which was inhibited by the pre-treatment of cells with neutralizing antibody against insulin-like growth factor 1 receptor (IGF-1R). Consistently, 232Th treatment was found to increase the phosphorylated level of IGF-1R-associated molecule, IRS1 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 232Th. Immunofluorescence analysis showed increased levels of phospho-Akt and phospho-JNK, downstream kinases of IGF-1R, in 232Th-treated HepG2 cells suggesting the role of IGF-1R-mediated signaling in 232Th-stimulated cell proliferation. The cell cycle analysis showed that 232Th increased S and G2-M cell fractions concomitant to the increase of cyclin-E level. Thus, the present investigation highlights the role of IGF-1R-mediated signaling in the cytoproliferative effect of 232Th in human liver cells at low concentration.
Journal: Chemico-Biological Interactions - Volume 211, 25 March 2014, Pages 29–35