Effects of MEK and DNMT inhibitors on arsenic-treated human uroepithelial cells in relation to Cyclin-D1 and p16.
Arsenic compounds are well-known toxic and carcinogenic agents, and they are widely distributed throughout the earth's crust. These compounds are associated with various human malignancies. It has been reported that there is an elevated risk of bladder cancer in an area highly contaminated with arsenic on the southwest coast of Taiwan. However, the underlying mechanisms of arsenic-associated carcinogenesis are still unclear. The cell cycle regulatory proteins are important indicators in control of cell cycle progression. Moreover, the high expression of Cyclin-D1 and loss of p16 has been associated with a worse prognosis in a variety of human cancers. Therefore, we investigated the effect of arsenic on Cyclin-D1 and p16 expression and evaluated the role of the ERK signaling pathway and DNA methylation in arsenic carcinogenesis. Our study results showed that Cyclin-D1 high expression was found in 56.3% (9/16) of urothelial carcinomas (UC) from a blackfoot disease (BFD) area and 6.3% (1/16) of UC from a non-BFD area (p=0.002). The p16 low expression in 81.2% (13/16) of UC from BFD areas was significantly lower than in non-BFD areas (25.0%; 4/16) (p=0.001). In addition, the Cyclin-D1 increased expression but decreased p16 expression in arsenite-treated SV-HUC-1 cells. However, when cells were pretreated with inhibitors (5-aza-CdR or U0126), the effects of arsenite on Cyclin-D1 and p16 expression were suppressed. Finally, these results indicated that Cyclin-D1 and p16 both might play important roles in carcinogenesis as a result of arsenic.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Ya-Chun
YC
Huang
Wen-Chun
WC
Hung
Wan-Tzu
WT
Chen
Wen-Hong
WH
Jiang
Hsin-Su
HS
Yu
Chee-Yin
CY
Chai
D020261:Arsenic Poisoning / Q000378:metabolism; D018053:Arsenites / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000096:biosynthesis*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009570:Nitriles / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014571:Urologic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D019459:Urothelium / Q000187:drug effects* / Q000378:metabolism
D018053:Arsenites; D002070:Butadienes; C530104:CCND1 protein, human; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D009570:Nitriles; C113580:U 0126; D019938:Cyclin D1; D000077209:Decitabine; D015254:DNA Modification Methylases; D020930:MAP Kinase Kinase Kinases; D001374:Azacitidine; C015001:arsenite