Proteomics identification of PGAM1 as a potential therapeutic target for urothelial bladder cancer.

Urothelial bladder cancer (UBC) is a major global health problem. There have been no major advances for the treatment of UBC in the last 30 years. In this study, we attempted to discover novel candidate therapeutic biomarkers for UBC. We utilized a two-dimensional polyacrylamide gel electrophoresis (2-DE) and ESI-Q-TOF MS/MS-based proteomic method to compare and identify differentially expressed proteins in UBC and adjacent normal tissues. Thirty five differentially expressed proteins (over 2-fold, p<0.05) were identified. Further cluster analysis revealed these proteins were mainly involved in metabolism, apoptosis regulation, calcium ion binding and so on. Among them, phosphoglycerate mutase 1 (PGAM1), significantly up-regulated in UBC, was selected for detailed analysis. Immunohistochemical data showed that increased expression of PGAM1 was correlated with the severity of histological grade. Knockdown of PGAM1 expression by RNAi contributed to a marked antitumor activity in vivo. Moreover, we found, upon attenuation of PGAM1, its substrate 3-PG (3-phosphoglycerate) was up-regulated and product 2-PG (2-phosphoglycerate) was down-regulated, which consequently inhibited aerobic glycolysis and oxidative pentose phosphate pathway (PPP) that are essential to cancer cell proliferation. Our finding showed that PGAM1 might serve as a promising therapeutic target for UBC.