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Proteomics identification of PGAM1 as a potential therapeutic target for urothelial bladder cancer
1Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Abstract:
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.
Insights
Researchers identified phosphoglycerate mutase 1 (PGAM1) as a potential therapeutic target for urothelial bladder cancer (UBC). Inhibiting PGAM1 showed significant antitumor activity by disrupting cancer cell metabolism and proliferation pathways.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Urothelial bladder cancer (UBC) lacks significant therapeutic advancements in recent decades.
- Identifying novel therapeutic biomarkers is crucial for improving UBC treatment outcomes.
Purpose of the Study:
- To discover novel candidate therapeutic biomarkers for urothelial bladder cancer (UBC).
- To investigate the potential of identified biomarkers as therapeutic targets.
Main Methods:
- Proteomic analysis using 2-DE and ESI-Q-TOF MS/MS to identify differentially expressed proteins in UBC tissues.
- Immunohistochemistry to correlate protein expression with tumor grade.
- RNA interference (RNAi) to assess the in vivo antitumor activity of targeted proteins.
Main Results:
- Thirty-five differentially expressed proteins were identified, with PGAM1 significantly upregulated in UBC.
- Increased PGAM1 expression correlated with higher histological grade.
- PGAM1 knockdown demonstrated significant in vivo antitumor activity, inhibiting aerobic glycolysis and the pentose phosphate pathway.
Conclusions:
- PGAM1 is a promising therapeutic target for urothelial bladder cancer.
- Targeting PGAM1 may offer a novel strategy for UBC treatment by disrupting key cancer cell metabolic pathways.
