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Title: Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells

Abstract

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 inmore » a tumor suppressor-like manner during early stages of Ni(II) carcinogenesis. - Highlights: • HIF-1α enhances growth arrest and senescence by Ni(II) in normal human cells. • HIF-1α is important for upregulation of the cell cycle inhibitors p21 and p27 in Ni(II)-treated normal cells. • Apoptotic responses and clonogenic toxicity by Ni(II) in transformed human cells are HIF-1α independent. • HIF-1α does not affect Ni(II) accumulation in normal or transformed human cells.« less

Authors:
;
Publication Date:
OSTI Identifier:
22722924
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 331; Conference: 9. conference on recent advances in metal toxicity and carcinogenesis research, Lexington, KY (United States), 1 Oct 2016; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL CELLS; ANOXIA; CELL CYCLE; CELL PROLIFERATION; INHIBITION; MONOCLINIC LATTICES; NICKEL; PHOSPHORUS 21; PLANT GROWTH; TOXICITY; TRANSCRIPTION FACTORS

Citation Formats

Luczak, Michal W., and Zhitkovich, Anatoly. Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.05.029.
Luczak, Michal W., & Zhitkovich, Anatoly. Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells. United States. doi:10.1016/J.TAAP.2017.05.029.
Luczak, Michal W., and Zhitkovich, Anatoly. Fri . "Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells". United States. doi:10.1016/J.TAAP.2017.05.029.
@article{osti_22722924,
title = {Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells},
author = {Luczak, Michal W. and Zhitkovich, Anatoly},
abstractNote = {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. - Highlights: • HIF-1α enhances growth arrest and senescence by Ni(II) in normal human cells. • HIF-1α is important for upregulation of the cell cycle inhibitors p21 and p27 in Ni(II)-treated normal cells. • Apoptotic responses and clonogenic toxicity by Ni(II) in transformed human cells are HIF-1α independent. • HIF-1α does not affect Ni(II) accumulation in normal or transformed human cells.},
doi = {10.1016/J.TAAP.2017.05.029},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 331,
place = {United States},
year = {2017},
month = {9}
}