The Warburg effect as a therapeutic target for bladder cancers and intratumoral heterogeneity in associated molecular targets

• Published in: Cancer science Vol. 112; no. 9; pp. 3822 - 3834
• Main Authors: Burns, Julie E., Hurst, Carolyn D., Knowles, Margaret A., Phillips, Roger M., Allison, Simon J.
• Format: Journal Article
• Language: English
• Published: Tokyo John Wiley & Sons, Inc 01.09.2021; John Wiley and Sons Inc
• Subjects: Analysis; Apoptosis; Bladder cancer; Cancer; Cancer therapies; Cell death; Chemotherapy; Dehydrogenases; Enzymes; epithelial‐mesenchymal transition; Experiments; FDA approval; Gene expression; Genomes; Glucose; Glucose metabolism; Glycolysis; Growth factors; Health aspects; intratumoral heterogeneity; Invasiveness; Kinases; L-Lactate dehydrogenase; lactate dehydrogenase A; Lactic acid; Mesenchyme; Metabolism; Mutation; non–muscle‐invasive and muscle‐invasive bladder cancers; Original; Patients; Phosphorylation; Proteins; Pyruvic acid; Radiation therapy; RNA-mediated interference; Therapeutic applications; Therapeutic targets; Tumor cell lines; Urothelial cancer; Warburg effect
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.15047

Bladder cancer is the 10th most common cancer worldwide. For muscle‐invasive bladder cancer (MIBC), treatment includes radical cystectomy, radiotherapy, and chemotherapy; however, the outcome is generally poor. For non–muscle‐invasive bladder cancer (NMIBC), tumor recurrence is common. There is an urgent need for more effective and less harmful therapeutic approaches. Here, bladder cancer cell metabolic reprogramming to rely on aerobic glycolysis (the Warburg effect) and expression of associated molecular therapeutic targets by bladder cancer cells of different stages and grades, and in freshly resected clinical tissue, is investigated. Importantly, analyses indicate that the Warburg effect is a feature of both NMIBCs and MIBCs. In two in vitro inducible epithelial‐mesenchymal transition (EMT) bladder cancer models, EMT stimulation correlated with increased lactate production, the end product of aerobic glycolysis. Protein levels of lactate dehydrogenase A (LDH‐A), which promotes pyruvate enzymatic reduction to lactate, were higher in most bladder cancer cell lines (compared with LDH‐B, which catalyzes the reverse reaction), but the levels did not closely correlate with aerobic glycolysis rates. Although LDH‐A is expressed in normal urothelial cells, LDH‐A knockdown by RNAi selectively induced urothelial cancer cell apoptotic death, whereas normal cells were unaffected—identifying LDH‐A as a cancer‐selective therapeutic target for bladder cancers. LDH‐A and other potential therapeutic targets (MCT4 and GLUT1) were expressed in patient clinical specimens; however, positive staining varied in different areas of sections and with distance from a blood vessel. This intratumoral heterogeneity has important therapeutic implications and indicates the possibility of tumor cell metabolic coupling. This work identifies aerobic glycolysis (the Warburg effect) as a general feature of both non–muscle‐invasive and muscle‐invasive bladder cancers. We further show that the glycolytic enzyme lactate dehydrogenase A is a cancer‐selective therapeutic target for bladder cancers, but that there is intratumoral heterogeneity in expression of metabolic targets. This raises the possibility of intratumoral metabolic coupling that could be therapeutically targeted.