A novel mechanism of methylglyoxal cytotoxicity in neuroglial cells

Authors: Lee, Hyun Kyoung¹; Seo, In Ae¹; Suh, Duk Joon¹; Lee, Hye Jeong²; Park, Hwan Tae¹

Source: Journal of Neurochemistry, Volume 108, Number 1, January 2009 , pp. 273-284(12)

Publisher: Wiley-Blackwell

Abstract:

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 H₂O₂ 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.

Keywords: cell death; cytokines; gp130; methylglyoxal; neuroglial cells; STAT3

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1471-4159.2008.05764.x

Affiliations: 1: Department of Physiology, Medical Science Research, Institute, College of Medicine, Dong-A University, Busan, South Korea 2: Department of Pharmacology, Medical Science Research, Institute, College of Medicine, Dong-A University, Busan, South Korea

Publication date: 2009-01-01

Related content

• In this: publication
• By this: publisher
• In this Subject: Anatomy & Physiology
• By this author: Lee, Hyun Kyoung ;  Seo, In Ae ;  Suh, Duk Joon ;  Lee, Hye Jeong ;  Park, Hwan Tae

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers