Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin

Abstract

Although numerous therapeutic strategies have attempted to target aerobic glycolysis to inhibit tumor progression, these approaches have not resulted in effective clinical outcomes. Murine squamous cell carcinoma (SCC) can be initiated by hair follicle stem cells (HFSCs). HFSCs utilize aerobic glycolysis, and the activity of lactate dehydrogenase (Ldh) is essential for HFSC activation. We sought to determine whether Ldh activity in SCC is critical for tumorigenesis or simply a marker of the cell type of origin. Genetic abrogation or induction of Ldh activity in HFSC-mediated tumorigenesis shows no effect on tumorigenesis as measured by number, time to formation, proliferation, volume, epithelial to mesenchymal transition, gene expression, or immune response. Ldha -null tumors show dramatically reduced levels of glycolytic metabolites by metabolomics, and significantly reduced glucose uptake by FDG-PET live animal imaging. These results suggest that squamous cancer cells of origin do not require increased glycolytic activity to generate cancers.

Copy number evolution and its relationship with patient outcome—an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial

“…We identified only a low frequency of CNAs to which IMiD response genes map. In conjuncture with published somatic SNV data, results suggest mutation of these genes per se is not the major determinant of acquired resistance to lenalidomide, or other members of this class of agent in MM [12,[14][15][16][33][34][35].…”

Association between lactate dehydrogenase levels and oncologic outcomes in metastatic prostate cancer: A meta‐analysis

“…Lactate dehydrogenase (LDH) is a glycolytic enzyme with five isozymes widely found in human tissues 11 . The tumor microenvironment plays a vital role in tumor prognosis 12 .…”

Oxidative Stress and the Intersection of Oncogenic Signaling and Metabolism in Squamous Cell Carcinomas

“…While redox homeostasis is accomplished primarily through glycolytic upregulation in SCC-specific metabolic programs, SCCs may also exploit amino acid transport to drive antioxidant anabolism and impart metabolic flexibility under glucose limiting conditions. Flores et al suggest that lactate dehydrogenase A (LDHA) and aerobic glycolysis may be dispensable in CSCCs as LDHA abrogation demonstrates no effect on tumor initiation or progression despite reduced glucose uptake and glycolytic intermediates [ 97 ]. However, they further demonstrate that LDHA -deficient tumors exhibited increased compensatory glutamine uptake, glutaminase activity, and reductive glutamine metabolism.…”