A novel mechanism of methylglyoxal cytotoxicity in neuroglial cells.
Methylglyoxal (MGO) is an endogenous dicarbonyl compound that is highly produced in hyperglycemic conditions. It forms advanced glycation endproducts that are believed to contribute, as etiological factors, to the pathophysiology of diabetic complications. In addition, MGO suppresses cell viability through the induction of apoptosis in vitro. In this study, we have, for the first time, demonstrated the effect of MGO on the gp130 cytokine-induced signal transducer and activator of transcription 3 (STAT3) responses in RT4 schwannoma, PC12 pheochromocytoma and U87MG glioma cells. At dose that very mildly affects cell viability, MGO rapidly induces endocytotic degradation of gp130, which involves the di-leucine internalization motif in the cytoplasmic domain of gp130, without affecting other growth factor receptors. Concomitant inhibition of basal and interleukin-6-induced STAT3 activation was observed following pre-treatment with MGO. The inhibitory effect of MGO on the gp130/STAT3 signaling was prevented by the pre-treatment with an advanced glycation endproduct scavenger aminoguanidine. Finally, these deleterious effects of MGO on STAT3 signaling led to down-regulation of a STAT3 target gene, Bcl-2, and sensitized cellular toxicity induced by H(2)O(2) and etoposide. Our data indicate that MGO affects cell viability via desensitization of gp130/STAT3 signaling, which is the key signaling pathway for cell survival, and thereby promotes cytotoxicity.
Lee
Hyun Kyoung
HK
Department of Physiology, Medical Science Research, Institute, College of Medicine, Dong-A University, Busan, South Korea.
Seo
In Ae
IA
Suh
Duk Joon
DJ
Lee
Hye Jeong
HJ
Park
Hwan Tae
HT
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012584:Sciatic Nerve / Q000166:cytology; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014162:Transfection / Q000379:methods
D000972:Antineoplastic Agents, Phytogenic; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D013778:Tetrazolium Salts; D013844:Thiazoles; D050822:Cytokine Receptor gp130; D005047:Etoposide; D011765:Pyruvaldehyde; D006861:Hydrogen Peroxide; C022616:thiazolyl blue