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Deoxynivalenol induced mouse skin tumor initiation: Elucidation of molecular mechanisms in human HaCaT keratinocytes
Author(s) -
Mishra Sakshi,
Tewari Prachi,
Chaudhari Bhushan P.,
Dwivedi Premendra D.,
Pandey Haushila P.,
Das Mukul
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30260
Subject(s) - hacat , superoxide dismutase , apoptosis , microbiology and biotechnology , downregulation and upregulation , p38 mitogen activated protein kinases , chemistry , oxidative stress , reactive oxygen species , kinase , biology , protein kinase a , biochemistry , gene , in vitro
Among food contaminants, mycotoxins are toxic to both human and animal health. Our prior studies suggest that Deoxynivalenol (DON), a mycotoxin, behaves as a tumor promoter by inducing edema, hyperplasia, ODC activity and activation of MAPK's in mouse skin. In this study, topical application of DON, 336 and 672 nmol significantly enhanced ROS levels, DNA damage and apoptosis with concomitant downregulation of Ki‐67, cyclin D, cyclin E, cyclin A and cyclin‐dependent kinases (CDK4 and CDK2) thereby resulting in tumor initiation in mouse skin. Further, the elucidation of molecular mechanisms of tumor initiation by DON (0.42–3.37 nmol/ml) in HaCaT keratinocytes, revealed ( i ) enhanced ROS generation with cell cycle phase arrest in G0/G1 phase, ( ii ) increase in levels of 8‐OxoG (6–24 hr) and γH2AX protein, ( iii ) significant enhancement in oxidative stress marker enzymes LPO, GSH, GR with concomitant decrease in antioxidant enzymes catalase, GPx, GST, SOD and mitochondrial membrane potential after DON (1.68 nmol) treatment, ( iv ) suppression of Nrf2 translocation to nucleus, enhanced phosphorylation with subsequent activation ERK1/2, p38 and JNK MAPK's following DON (1.68 nmol) treatment, ( v ) overexpression of c‐jun, c‐fos proteins, upregulation of Bax along with downregulation of Bcl‐2 proteins, ( vi ) increase in cytochrome‐c, caspase‐9, caspase‐3 and poly ADP ribose polymerase levels leads to apoptosis. Pretreatment of superoxide dismutase, mannitol and ethanol to HaCaT cells resulted in significant reduction in ROS levels and apoptosis indicating the role of superoxide and hydroxyl radicals in DON induced apoptosis as an early event and skin tumor initiation as a late event.