Dicarbonyl-mediated protein modifications affect matrix metalloproteinase (MMP) activity

Abstract

Advanced age is linked with an increased incidence of epithelial tumours (carcinomas) including lung tumours. However, a slowing rate of the increase of age-specific cancer incidence is demonstrated at very advanced ages, and elderly patients also develop less invasive and metastatic tumours than their younger counterparts. Matrix metalloproteinases (MMPs) are commonly upregulated in the stromal compartment of the carcinoma tissue and are believed to promote invasion and metastasis. As the increased serum and tissue level of advanced glycation end products (AGEs) is a characteristic feature of old humans, our study focused on the impact of AGEs on the activity of MMPs released from lung fibroblasts (WI- 38). The collagen gel zymography technique showed the primary presence of MMP-2 in the conditioned medium of the WI-38 fibroblasts, which was even higher in senescent WI-38 fibroblasts. Subsequent treatment of the WI- 38 conditioned medium with the dicarbonyl compound glyoxal, a highly reactive precursor of the AGE formation, resulted in a dose-dependent reduction of the MMP-2 activity. Therefore, our study suggests that the age-associated increase in AGEs might be one potential host factor responsible for the less invasiveness of tumours at very advanced age.