Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells
| Autor: | Michal W. Luczak, Anatoly Zhitkovich |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CDC25A Cell Survival Cell Biology Toxicology medicine.disease_cause Article 03 medical and health sciences Nickel Cyclin-dependent kinase medicine Humans Cellular Senescence Cell Line Transformed Pharmacology Dose-Response Relationship Drug Cell growth Cell Cycle Checkpoints Cell cycle Hypoxia-Inducible Factor 1 alpha Subunit Growth Inhibitors Cell biology 030104 developmental biology medicine.anatomical_structure HIF1A A549 Cells Cancer cell biology.protein Carcinogenesis |
| Zdroj: | Toxicology and Applied Pharmacology. 331:94-100 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2017.05.029 |
| Popis: | Nickel is a human carcinogen that acts as a hypoxia mimic by activating the transcription factor HIF-1α and hypoxia-like transcriptomic responses. Hypoxia and elevated HIF-1α are typically associated with drug resistance in cancer cells, which is caused by increased drug efflux and other mechanisms. Here we examined the role of HIF-1α in uptake of soluble Ni(II) and Ni(II)-induced cell fate outcomes using si/shRNA knockdowns and gene deletion models. We found that HIF-1α had no effect on accumulation of Ni(II) in two transformed (H460, A549) and two normal human cell lines (IMR90, WI38). The loss of HIF-1α also produced no significant impact on p53-dependent and p53-independent apoptotic responses or clonogenic survival of Ni(II)-treated transformed cells. In normal human cells, HIF-1α enhanced the ability of Ni(II) to inhibit cell proliferation and cause a permanent growth arrest (senescence). Consistent with its growth-suppressive effects, HIF-1α was important for upregulation of the cell cycle inhibitors p21 (CDKN1A) and p27 (CDKN1B). Irrespective of HIF-1α status, Ni(II) strongly increased levels of MYC protein but did not change protein expression of the cell cycle-promoting phosphatase CDC25A or the CDK inhibitor p16. Our findings indicate that HIF-1α limits propagation of Ni(II)-damaged normal cells, suggesting that it may act in a tumor suppressor-like manner during early stages of Ni(II) carcinogenesis. |
| Databáze: | OpenAIRE |
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