Interplay between cellular methyl metabolism and adaptive efflux during oncogenic transformation from chronic arsenic exposure in human cells.
After protracted low level arsenic exposure, the normal human prostate epithelial cell line RWPE-1 acquires a malignant phenotype with DNA hypomethylation, indicative of disrupted methyl metabolism, and shows arsenic adaptation involving glutathione overproduction and enhanced arsenic efflux. Thus, the interplay between methyl and glutathione metabolism during this progressive arsenic adaptation was studied. Arsenic-treated cells showed a time-dependent increase in LC50 and a marked increase in homocysteine (Hcy) levels. A marked suppression of S-adenosylmethionine (SAM) levels occurred with decreased methionine adenosyltransferase 2A (converts methionine to SAM) expression and increased negative regulator methionine adenosyltransferase B, suggesting reduced conversion of Hcy to SAM. Consistent with Hcy overproduction, activity and expression of S-adenosylhomocysteine hydrolase (converts S-adenosylhomocysteine to Hcy) were both increased. Expression of cystathionine beta-synthase, a key gene in the transsulfuration pathway, and various glutathione production genes were increased, resulting in a 5-fold increase in glutathione. Arsenic efflux increased along with expression of ATP-binding cassette protein C1, which effluxes arsenic as a glutathione conjugate. Evidence of genomic DNA hypomethylation was observed during early arsenic exposure, indicating that the disruption in methyl metabolism had a potential impact related to oncogenesis. Thus, cellular arsenic adaptation is a dynamic, progressive process that involves decreased SAM recycling and concurrent accumulation of Hcy, which is channeled via transsulfuration to increase glutathione and enhance arsenic efflux but may also impact the carcinogenic process.
Coppin
Jean-François
JF
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Qu
Wei
W
Waalkes
Michael P
MP
D043383:Adenosylhomocysteinase / Q000096:biosynthesis; D018053:Arsenites / Q000494:pharmacology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D003541:Cystathionine beta-Synthase / Q000096:biosynthesis; D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D008297:Male; D008716:Methionine Adenosyltransferase / Q000096:biosynthesis; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D011467:Prostate / Q000201:enzymology* / Q000473:pathology; D012436:S-Adenosylmethionine / Q000378:metabolism; D017670:Sodium Compounds / Q000494:pharmacology*
D043383:Adenosylhomocysteinase; D018053:Arsenites; D003541:Cystathionine beta-Synthase; D004791:Enzyme Inhibitors; D005978:Glutathione; D006710:Homocysteine; D008716:Methionine Adenosyltransferase; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012436:S-Adenosylmethionine; D017670:Sodium Compounds; C017947:sodium arsenite; C527161:MAT2A protein, human; C421109:multidrug resistance-associated protein 1