Thorium induced cytoproliferative effect in human liver cell HepG2: role of insulin-like growth factor 1 receptor and downstream signaling.
Thorium-232 ((232)Th), 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 (232)Th would significantly impact its efficient utilization with adequate health protection. Humans administered with (232)Th (thorotrast patients) or experimental animal models showed that liver is one of the major sites of (232)Th accumulation. Present study reports cellular effects of (232)Th-nitrate in a human-derived liver cell (HepG2). Results showed that the low concentration of (232)Th (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, (232)Th 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 (232)Th. Immunofluorescence analysis showed increased levels of phospho-Akt and phospho-JNK, downstream kinases of IGF-1R, in (232)Th-treated HepG2 cells suggesting the role of IGF-1R-mediated signaling in (232)Th-stimulated cell proliferation. The cell cycle analysis showed that (232)Th 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 (232)Th in human liver cells at low concentration.
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.
Manjoor
M
Ali
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India. Electronic address: amitk@barc.gov.in.
Amit
A
Kumar
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.
Badri N
BN
Pandey
D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D017970:Thorium Compounds / Q000633:toxicity*
D004791:Enzyme Inhibitors; D017970:Thorium Compounds; D017526:Receptor, IGF Type 1; C036680:thorium nitrate
Akt and MAPK; Cyclin-E; Cytoproliferative effect; IGF-1R; Thorium