HO-1 Modulates Aerobic Glycolysis through LDH in Prostate Cancer Cells

Abstract

Prostate cancer (PCa) is the second most diagnosed malignancy and the fifth leading cause of cancer associated death in men worldwide. Dysregulation of cellular energetics has become a hallmark of cancer, evidenced by numerous connections between signaling pathways that include oncoproteins and key metabolic enzymes. We previously showed that heme oxygenase 1 (HO-1), a cellular homeostatic regulator counteracting oxidative and inflammatory damage, exhibits anti-tumoral activity in PCa cells, inhibiting cell proliferation, migration, tumor growth and angiogenesis. The aim of this study was to assess the role of HO-1 on the metabolic signature of PCa. After HO-1 pharmacological induction with hemin, PC3 and C4-2B cells exhibited a significantly impaired cellular metabolic rate, reflected by glucose uptake, ATP production, lactate dehydrogenase (LDH) activity and extracellular lactate levels. Further, we undertook a bioinformatics approach to assess the clinical significance of LDHA, LDHB and HMOX1 in PCa, identifying that high LDHA or low LDHB expression was associated with reduced relapse free survival (RFS). Interestingly, the shortest RFS was observed for PCa patients with low HMOX1 and high LDHA, while an improved prognosis was observed for those with high HMOX1 and LDHB. Thus, HO-1 induction causes a shift in the cellular metabolic profile of PCa, leading to a less aggressive phenotype of the disease.

Anticancer potential of phytochemicals from Oroxylum indicum targeting Lactate Dehydrogenase A through bioinformatic approach

“…Glycolysis is the breakdown of a whole glucose molecule into two pyruvate molecules. In cancer cells, glycolysis process breaks down glucose molecules partially and produces pyruvate molecules which are then transformed into lactate via a metabolic mechanism catalyzed by Lactate Dehydrogenase (LDH) enzyme [3] . This lactate synthesis is responsible for increased glycolysis, which contributes significantly to cancer growth and progression by lowering the pH for invasion, replenishing NAD+ for glycolysis, and inducing immune escape [4] .…”

The Integration of Metabolomics with Other Omics: Insights into Understanding Prostate Cancer

“…The decrease in citrate lowers NADH production [81,273]. As a result, PCa cells produce energy less efficiently [274][275][276][277][278]. The accretion of zinc in normal prostate inhibits m-aconitase (m-ACO), the enzyme that catalyzes the isomerization of citrate to isocitrate in the TCA cycle [81,273].…”

Preparation of a Mesoporous Biosensor for Human Lactate Dehydrogenase for Potential Anticancer Inhibitor Screening

“…Moreover, pancreatic cancer is one of the most lethal . The cells of all these cancer typologies are subjected to aerobic glycolysis or Warburg effect. − As a whole, cancer cells metabolize glucose into pyruvic acid and then convert it to lactate, even in the presence of oxygen. As schematized in Figure , healthy cells transform pyruvate into lactate only under hypoxic conditions.…”