Inhibition of LDHA suppresses cell proliferation and increases mitochondrial apoptosis via the JNK signaling pathway in cervical cancer cells

The Warburg effect or aerobic glycolysis is a hallmark of cancer. Lactate dehydrogenase (LDH), which catalyzes conversion of pyruvate into lactate, serves a critical role during Warburg effect. LDH A chain (LDHA), a member of the LDH family, is upregulated in multiple types of cancer and serves a vital role in tumor growth and progression. However, its expression and function in cervical cancer has not been characterized. The present study evaluated LDHA expression in The Cancer Genome Atlas database and found that LDHA was upregulated in cervical cancer compared with normal tissue. To clarify the role of LDHA in cervical cancer HeLa and SiHa cells, lentiviral shRNA was used to stably knockdown LDHA and oxamate, a small-molecule inhibitor of LDHA, was used to inhibit the activity of LDHA. Glucose uptake assay, lactate production measurement and ATP detection assay demonstrated LDHA inhibition notably decreased glucose consumption, lactate production and ATP levels in both HeLa and SiHa cells. Furthermore, the effect of LDHA inhibition on cell proliferation, cell cycle and apoptosis was investigated by MTT, BrdU incorporation, colony formation assay, flow cytometry and western blotting; LDHA knockdown or oxamate treatment led to decreased cell proliferation and increased apoptosis. Inhibition of LDHA induced G(2)/M cell cycle arrest and activated the mitochondrial apoptosis pathway. Mechanistically, the JNK signaling pathway was key for LDHA inhibition-mediated cell cycle arrest and apoptosis. Collectively, these results indicated that LDHA was involved in cervical cancer pathogenesis and may be a promising therapeutic target for treatment.

Automated summary

LDHA is upregulated in cervical cancer and its inhibition leads to reduced glucose consumption, lactate production, cell proliferation, and enhanced apoptosis. LDHA inhibition also affects cell cycle and mitochondrial apoptosis pathway.