Arsenic-induced cell proliferation is associated with enhanced ROS generation, Erk signaling and CyclinA expression.
Arsenic is a well-established human carcinogen; however molecular mechanisms to arsenic-induced carcinogenesis are complex and elusive. The present study identifies a potential biomarker of arsenic exposure, and redefines arsenic-induced signaling in stimulation of cell proliferation. The effect of arsenic exposure on gene expression was evaluated in PBMC of arsenic-exposed individuals selected from a severely affected district of West Bengal, India. A novel, un-documented biomarker of arsenic exposure, CyclinA was identified by microarray analysis from the study. Non-transformed cell lines HaCat and Int407 when exposed to clinically achievable arsenic concentration showed significant increase of CyclinA substantiating the clinical data. An associated increase in S phase population of cells in cell cycle, indicative of enhanced proliferation was also noticed. On further investigation of the pathway to arsenic-induced proliferation, we observed that arsenic resulted: ROS generation; activated Erk signaling; stimulated AP-1 activity, including immediate early genes, c-Jun and c-Fos. N-Acetyl-l-cysteine, a ROS quencher, blocked the arsenic-induced effects. Our study underlines a previously undefined mechanism by which arsenic imparts its toxicity and results in uncontrolled cell proliferation.
Chowdhury
Rajdeep
R
Molecular & Human Genetics Division, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700032, India.
Chatterjee
Raghunath
R
Giri
Ashok K
AK
Mandal
Chitra
C
Chaudhuri
Keya
K
D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity*; D018053:Arsenites / Q000633:toxicity; D015153:Blotting, Western; D002274:Carcinogens, Environmental / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity*; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003001:Cloning, Molecular; D019925:Cyclin A / Q000096:biosynthesis / Q000235:genetics*; D004781:Environmental Exposure / Q000032:analysis; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006197:Hair / Q000737:chemistry; D006801:Humans; D007194:India; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000235:genetics; D009262:Nails / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012871:Skin Diseases / Q000139:chemically induced / Q000453:epidemiology; D017670:Sodium Compounds / Q000633:toxicity; D014162:Transfection; D014874:Water Pollutants, Chemical / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity*
D018053:Arsenites; D002274:Carcinogens, Environmental; D019925:Cyclin A; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; D014874:Water Pollutants, Chemical; C017947:sodium arsenite; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases; D001151:Arsenic