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Title: Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response

Abstract

Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100 nM, 30 weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100 nM) did not induce ODD during the 30 weeks required for malignant transformation. Although acute UV-treatment (UVA, 25 J/cm{sup 2}) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (> 50%). Despite enhanced ODD, As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes (HO-1, GCLs, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposuremore » enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD. - Highlights: > Arsenic transformation adapted to UV-induced apoptosis. > Arsenic transformation diminished oxidant response. > Arsenic transformation enhanced UV-induced DNA damage.« less

Authors:
;  [1]; ;  [2];  [3]
  1. Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute of Environmental Health Sciences, and National Toxicology Laboratories, National Toxicology Program, the National Institutes of Health, Research Triangle Park, NC 27709 (United States)
  2. Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709 (United States)
  3. Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute of Environmental Health Sciences, and National Toxicology Laboratories, National Toxicology Program, National Institutes of Health, Research Triangle Park, NC 27709 (United States)
Publication Date:
OSTI Identifier:
21587840
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 255; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2011.07.006; PII: S0041-008X(11)00266-3; Copyright (c) 2011 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; APOPTOSIS; ARSENIC; CARCINOGENESIS; CARCINOGENS; DNA DAMAGES; NEOPLASMS; OXIDATION; SKIN; STRESSES; BODY; CHEMICAL REACTIONS; DISEASES; ELEMENTS; ORGANS; PATHOGENESIS; SEMIMETALS

Citation Formats

Sun Yang, Kojima, Chikara, Chignell, Colin, Mason, Ronald, and Waalkes, Michael P., E-mail: waalkes@niehs.nih.gov. Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response. United States: N. p., 2011. Web.
Sun Yang, Kojima, Chikara, Chignell, Colin, Mason, Ronald, & Waalkes, Michael P., E-mail: waalkes@niehs.nih.gov. Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response. United States.
Sun Yang, Kojima, Chikara, Chignell, Colin, Mason, Ronald, and Waalkes, Michael P., E-mail: waalkes@niehs.nih.gov. Thu . "Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response". United States.
@article{osti_21587840,
title = {Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response},
author = {Sun Yang and Kojima, Chikara and Chignell, Colin and Mason, Ronald and Waalkes, Michael P., E-mail: waalkes@niehs.nih.gov},
abstractNote = {Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100 nM, 30 weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100 nM) did not induce ODD during the 30 weeks required for malignant transformation. Although acute UV-treatment (UVA, 25 J/cm{sup 2}) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (> 50%). Despite enhanced ODD, As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes (HO-1, GCLs, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposure enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD. - Highlights: > Arsenic transformation adapted to UV-induced apoptosis. > Arsenic transformation diminished oxidant response. > Arsenic transformation enhanced UV-induced DNA damage.},
doi = {},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 255,
place = {United States},
year = {2011},
month = {9}
}