Inorganic arsenic trioxide induces gap junction loss in association with the downregulation of connexin43 and E-cadherin in rat hepatic "stem-like" cells.
Chronic exposure to inorganic arsenic trioxide causes tumors of the skin, urinary bladder, lung, and liver. Several cancer initiators and promoters have been shown to alter cell-cell signaling by interference with gap junction intercellular communication (GJIC) and/or modulation of cell adhesion molecules, such as connexin43 (Cx43), E-cadherin, and β-catenin. The aim of this study was to determine whether the disruption of cell-cell interactions occurs in liver epithelial cells after exposure to arsenic trioxide. WB-F344 cells were treated with arsenic trioxide (6.25-50 μM) for up to 8 hours, and gap junction function was analyzed using the scrape-load/dye transfer assay. In addition, the changes in mRNA and protein levels of Cx43, E-cadherin, and β-catenin were determined. A significant dose- and time-dependent decrease in GJIC was observed when WB-F344 cells were exposed to arsenic trioxide (p < 0.05). Consistent with the inhibition of GJIC, cells' exposure to arsenic trioxide resulted in dose- and time-dependent decreases in Cx43 and E-cadherin mRNA expression and protein levels. However, arsenic trioxide did not alter the mRNA or protein levels of β-catenin. In an immunofluorescence study, nuclei were heavily stained with anti-β-catenin antibody, indicating significant nuclear translocation. In this study, we also demonstrated that arsenic trioxide-induced GJIC loss was a reversible process. Taken together, these data support the hypothesis that disruption of cell-cell communication may contribute to the tumor-promoting effect of inorganic arsenic trioxide.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Pi-Jung
PJ
Hsiao
College of Health Science, Kaohsiung Medical University, Department of Medical Imaging and Radiological Sciences, Kaohsiung, Taiwan.
Jo-Chi
JC
Jao
Graduate Institute of Occupational Safety, Kaohsiung Medical University, Kaohsiung, Taiwan.
Jin-Lian
JL
Tsai
Division of Hepatobiliopancreatic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Wen-Tsan
WT
Chang
Department of Surgery, Far Eastern Memorial Hospital, Taipei, Taiwan.
Kuo-Shyang
KS
Jeng
Division of Hepatobiliopancreatic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Electronic address: kuoksfo@yahoo.com.tw.
Kung-Kai
KK
Kuo
D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism*; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism*; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism*; D008099:Liver / Q000166:cytology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D051381:Rats
D001152:Arsenicals; D015820:Cadherins; D018031:Connexin 43; D010087:Oxides; D000077237:Arsenic Trioxide
Arsenic toxicity; Carcinogenesis; Liver cancer stem cell