Sodium arsenite inhibits and reverses expression of adipogenic and fat cell-specific genes during in vitro adipogenesis.
Arsenic causes cancer in humans, but its mechanism of action is unique among known carcinogenic agents. As a naturally occurring component of sediments and ground water, human exposure to arsenic is inevitable, necessitating the establishment of exposure limits. Because cancer is characterized as an imbalance between cell growth and differentiation, it has been hypothesized that arsenic exerts its carcinogenic effect, in part, by perturbing the balance between these antagonistic processes. Previous work in this laboratory has demonstrated that sodium arsenite prevents adipocytic differentiation of C3H 10T1/2 cells, leading to the hypothesis that the underlying mechanism involves downregulation of genes associated with adipogenesis. In support of this hypothesis, it was found that mRNA levels of peroxisome proliferative-activated receptor gamma (PPAR gamma), CCAAT-enhancer binding protein alpha (C/EBP alpha), and adipocyte-selective, fatty acid-binding protein (aP2) are decreased in arsenic-treated cells; arsenic-induced phenotypic reversion of differentiated adipocytes correlates with reduced aP2 expression. Arsenic also blocks upregulation of p21(Cip1/Waf1), a factor whose expression is tightly regulated during adipogenesis. The differentiating effect of pioglitazone, which induces adipogenesis by activating PPAR gamma, is inhibited by arsenic, suggesting that arsenic interferes with adipogenic signaling at or below the level of PPAR gamma. Because C/EBP alpha is important in the expression of certain keratinocyte-specific genes, the negative effect of arsenic on C/EBP alpha might also contribute to the development of skin cancer. PPAR gamma, C/EBP alpha, and p21(Cip1/Waf1) are important in numerous normal and pathological processes, including carcinogenesis, leading us to postulate that perturbation of these factors by arsenic might contribute to the carcinogenic effect of this metalloid.
Wauson
Eric M
EM
Center for Environmental Toxicology and Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6260, USA.
Langan
Amy S
AS
Vorce
Roseann L
RL
D017667:Adipocytes / Q000187:drug effects*; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D018053:Arsenites / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004336:Drug Antagonism; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D017670:Sodium Compounds / Q000633:toxicity*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
D000943:Antigens, Differentiation; D018053:Arsenites; D002273:Carcinogens; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D017670:Sodium Compounds; C493668:Tfap2a protein, mouse; D013844:Thiazoles; D045162:Thiazolidinediones; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C017947:sodium arsenite; D000077205:Pioglitazone