Statins inhibit the growth of variant human embryonic stem cells and cancer cells in vitro but not normal human embryonic stem cells
| Autor: | K Gauthaman, N Manasi, Ariff Bongso |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Homeobox protein NANOG
Antineoplastic Agents Biology Adenocarcinoma Cell Line Mevastatin Cell Line Tumor medicine Humans Embryonic Stem Cells Cell Proliferation Pharmacology Cell growth Cell Cycle Genetic Variation Cell cycle Embryonic stem cell Research Papers Growth Inhibitors Biochemistry Cell culture Cancer cell Cancer research lipids (amino acids peptides and proteins) Stem cell Hydroxymethylglutaryl-CoA Reductase Inhibitors medicine.drug |
| Popis: | Background and purpose: Statins inhibit proliferation of various human cancer cell lines in vitro. As human embryonic stem cells (hESCs) possess neoplastic-like properties we have evaluated the role of various statins on karyotypically normal hESCs (HES3 and BG01), abnormal hESCs (BG01V) and breast adenocarcinoma cells (MCF-7) to evaluate whether the mode of action of the statins was via a stemness pathway. Experimental approach: All cell lines were treated with simvastatin, pravastatin, lovastatin and mevastatin (1 µmol·L−1 to 20 µmol·L−1) up to 7 days and their effects on cell proliferation, cell cycle, apoptosis and pluripotency studied. Key results: All four statins did not inhibit HES3 and BG01 proliferation, but BG01V and MCF-7 were inhibited by simvastatin, lovastatin and mevastatin. These inhibitory effects were reversed by the endogenous isoprenoids, farnesylpyrophosphate and geranylgeranylpyrophosphate. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling and cell cycle assay confirmed apoptosis in BG01V and MCF-7. Stem cell surface markers [stage-specific embryonic antigen-4, tumour rejection antigen-1-81, octamer-4 (OCT-4)] were expressed in HES3 and BG01, but not in BG01V cells, even after prolonged treatment with simvastatin. In BG01V and MCF-7, the pro-apoptotic Bcl-2-associated X protein genes were up-regulated, while the antiapoptotic BCL2 and SURVIVIN genes were down-regulated. Expression of the stemness-related genes namely, the growth differentiation factor-3, NANOG and OCT-4 was decreased in BG01V compared with BG01 and HES3. Conclusions and implications: Normal hESCs were resistant to prolonged exposure to statins over a range of doses, compared with BG01V and MCF-7, probably because of genetic and behavioural differences. The statins not only have anti-cancer properties but can suppress abnormal hESCs thus promoting growth of normal hESCs in vitro. |
| Databáze: | OpenAIRE |
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