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.