Warburg Effect and Cancer Survival

Abstract

Warburg effect is a major metabolic shift of glycolysis in cancer cells towards anaerobic fermentation. Key reaction here overproduces lactate from pyruvate catalyzed by lactate dehydrogenase-A (LDHA). Augmented Warburg effect and oncometabolism may contribute to cancer progression worsening patients’ survival. Expressions of various key enzymes were used as surrogates to validate the clinical influence of metabolic alterations in cancers. Expression and Kaplan-Meier survival data were extracted from the R2 Genomics Analysis and Visualization Platform (R2) and Human Protein Atlas (HPA). Expression of LDHA gene was 2-4 times higher than normal tissues in certain cancers including breast, colon, genitourinary and B-cell lymphomas. No cancer specificity or strong associations were observed between RNA and protein expressions of LDHA. However, higher LDHA gene expression correlated with poorer survival in renal, liver, lung, pancreatic, cervical and breast cancers. These cancers moderately or strongly stained for LDHA protein. Per HPA, gliomas had low LDHA without survival correlation. Nevertheless, this correlation was observed in the largest glioblastoma database (R2). Furthermore, 3 of 4 medulloblastoma subtypes showed poor survival with higher LDHA. Contrarily, in B-cell lymphomas and colon cancer high LDHA was a favorable prognostic marker. Poor survival correlated with high expression of other enzymes for glycolysis and amino acid metabolism (PFK-isoenzymes, GFPT2 and BCAT1). Warburg effect may not be universally dominant for all cancers, but most cancers have high LDHA and/or associated poor survival, confirming importance of this metabolic derangement in cancers. Heterogeneity of metabolic alterations can serve to diversify anti-metabolic strategies for targeted anti-cancer therapies.