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Argpyrimidine-modified Heat shock protein 27 in human non-small cell lung cancer: a possible mechanism for evasion of apoptosis.

Abstract
Tumors generally display a high glycolytic rate. One consequence of increased glycolysis is the non-enzymatic glycation of proteins leading to the formation of advanced glycation end-products (AGEs). Therefore, we studied the presence of AGEs in non-small cell lung cancer and consequences thereof. We show the presence of two AGEs, i.e. the major AGE N(epsilon)-(carboxymethyl)lysine (CML) and the methylglyoxal-arginine adduct argpyrimidine, in human non-small cell lung cancer tissues by immunohistochemistry. We found in squamous cell carcinoma and adenocarcinoma tissues a strong CML positivity in both tumour cells and tumour-surrounding stroma. In contrast, argpyrimidine positivity was predominantly found in tumor cells and was strong in squamous cell carcinomas, but only weak in adenocarcinomas (2.6+/-0.5 vs. 1.2+/-0.4, respectively; P<0.005). In accordance, argpyrimidine was found in the human lung squamous carcinoma cell line SW1573, while it was almost absent in the adenocarcinoma cell line H460. Heat shock protein 27 (Hsp27) was identified as a major argpyrimidine-modified protein. In agreement with a previously described anti-apoptotic activity of argpyrimidine-modified Hsp27, the percentage of active caspase-3 positive tumor cells in squamous cell carcinomas was significantly lower when compared to adenocarcinomas. In addition, incubation with cisplatin induced almost no caspase-3 activation in SW1573 cells while a strong activation was seen in H460 cells; which was significantly reduced by incubation with an inhibitor of glyoxalase I, the enzyme that catalyzes the conversion of methylglyoxal. These findings suggest that a high level of argpyrimidine-modified Hsp27 is a mechanism of cancer cells for evasion of apoptosis.
AuthorsJeroen W J van Heijst, Hans W M Niessen, Rene J Musters, Victor W M van Hinsbergh, Klaas Hoekman, Casper G Schalkwijk
JournalCancer letters (Cancer Lett) Vol. 241 Issue 2 Pg. 309-19 (Sep 28 2006) ISSN: 0304-3835 [Print] Ireland
PMID16337338 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Glycation End Products, Advanced
  • Heat-Shock Proteins
  • Pyrimidines
  • argpyrimidine
  • Ornithine
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Glucose
Topics
  • Adenocarcinoma (drug therapy, metabolism, pathology)
  • Apoptosis (drug effects)
  • Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
  • Carcinoma, Squamous Cell (drug therapy, metabolism, pathology)
  • Caspase 3
  • Caspases (metabolism)
  • Enzyme-Linked Immunosorbent Assay
  • Glucose (metabolism)
  • Glycation End Products, Advanced (metabolism)
  • Glycolysis
  • Heat-Shock Proteins (metabolism)
  • Humans
  • Lung Neoplasms (drug therapy, metabolism, pathology)
  • Ornithine (analogs & derivatives, pharmacology)
  • Pyrimidines (pharmacology)
  • Tumor Cells, Cultured

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