Koningic acid reduces tumor activity in neuroendocrine prostate cancer by inhibiting glycolysis

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer with poor prognosis and limited therapeutic options. Targeting cancer metabolism is a promising strategy for treating NEPC. This study investigated the antitumor activity and underlying mechanisms of koningic acid (KA), a selective glyceraldehyde-3-phosphate dehydrogenase inhibitor, in NEPC. NEPC cell models (PC3, LNCaP-NE, and NCI-H660) were treated with KA to assess its effects on cell viability, colony formation, glycolysis, mitochondrial function, and apoptosis. Xenograft models were used to evaluate in vivo tumor growth. Key markers and pathways were analyzed using quantitative polymerase chain reaction, western blotting, and immunohistochemistry. In this study, KA significantly inhibited cell proliferation and colony formation, with IC50 values of 5.73 μM in PC3, 7.57 μM in LNCaP-NE, and 6.32 μM in NCI-H660 cells. Glycolysis was markedly suppressed, as indicated by reduced extracellular acidification rate, lactate production, and glucose uptake. KA also induced mitochondrial dysfunction, evidenced by decreased mitochondrial membrane potential, increased reactive oxygen species, and reduced ATP levels. Furthermore, KA decreased phospho (p)-Akt and p-glycogen synthase kinase-3β expression, leading to apoptosis activation. In xenograft models, KA treatment reduced tumor size, weight, and expression of Ki67, p-Akt, and of lactate dehydrogenase A, while increasing levels of apoptosis markers. In conclusion, KA exerts significant antitumor effects in NEPC by inhibiting glycolysis and inducing mitochondrial apoptosis. These findings highlight its potential as a therapeutic agent for NEPC. SIGNIFICANCE STATEMENT: Koningic acid (KA) inhibits glycolysis and suppresses proliferation in neuroendocrine prostate cancer cells by targeting glyceraldehyde-3-phosphate dehydrogenase. KA induces mitochondrial dysfunction, increases reactive oxygen species production, and activates apoptosis through downregulation of phospho-Akt and phospho-glycogen synthase kinase-3β signaling. In vivo studies demonstrate that KA reduces tumor growth and proliferation while promoting apoptosis, highlighting its potential as a therapeutic agent for neuroendocrine prostate cancer.