Advanced glycation end products down-regulate gap junctions in human hepatoma SKHep 1 cells via the activation of Src-dependent ERK1/2 and JNK/SAPK/AP1 signaling pathways.
Hyperglycemia and advanced glycation end products (AGEs) are associated with an elevated risk of developing several cancers in diabetic patients. However, the detailed mechanisms remain to be elucidated. The mechanism of AGE-bovine serum albumin (BSA) on gap junction intercellular communication in human hepatoma cell line, SKHep 1, was investigated. Both Cx32 and Cx43 are major gap junction forming proteins in the liver, the loss of which has been shown to facilitate tumorigenesis. Although the MTT assay results showed that AGE-BSA significantly increased cell growth by 31%, AGE-BSA down-regulated Cx32 and Cx43 expression in a dose- and time-dependent manner. The present study also demonstrated that ERK1/2 and JNK/SAPK were significantly activated by AGE-BSA and that Src, ERK1/2, and JNK/SAPK inhibitors significantly reversed the reduction of Cx32 and Cx43 proteins by AGE-BSA. Taken together, these results strongly support the hypothesis that Src-dependent ERK1/2 and JNK/SAPK/AP1 signaling pathways play a key role in AGE-BSA-mediated down-regulation of Cx32 and Cx43 protein expression in SKHep 1 cells.
Lin
Feng L
FL
Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan.
Chang
Chi I
CI
Chuang
Kuo Pin
KP
Wang
Chi Y
CY
Liu
Hung J
HJ
D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D016759:Oncogene Protein p65(gag-jun) / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
D017127:Glycation End Products, Advanced; D016759:Oncogene Protein p65(gag-jun); D018808:Transcription Factor AP-1; D016392:Proto-Oncogene Proteins pp60(c-src); D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4