Journal Article

Triclabendazole inhibits PKM2 nuclear localization and glycolysis by enhancing HDAC6-mediated deacetylation in lung cancer

Li, Yuan, Qu, Liang-zhuo, Fan, Jun, Zhang, Yi-fan, Liu, Jing, Yan, Liang, Sun, Yong, Shi, Shan-shan, Zha, Qing-bing, Dai, Yong

2025

Overview

Background Metabolic reprogramming is a hallmark of cancer cells, enabling them to meet the heightened energetic and biosynthetic demands required for rapid growth and proliferation. Recently, non-canonical functions of metabolic enzymes have garnered significant attention in cancer research. Pyruvate kinase 2 (PKM2) has been identified as a key player in transcriptional regulation within the nucleus, presenting new opportunities for therapeutic interventions in cancer. Methods In this study, the cells (A549 and H1299) were treated with indicator concentration of triclabendazole. The effects of triclabendazole on proliferation was detected by CCK8 assay, colony formation assay, EdU staining, and cell count assay. A tumorigenesis study in nude mice was performed to demonstrate the inhibitory effect of triclabendazole on tumor growth. PKM2 nuclear translocation, HDAC6-mediated deacetylation, glycolytic flux downregulation, and activation of AMPK/mTOR signaling pathway were used to elucidate the mechanistic role of triclabendazole in lung cancer progression. Results This study discovered that triclabendazole, a novel benzimidazole derivative, commonly used against Fasciola hepatolithiasis , effectively inhibited the nuclear translocation of PKM2. This inhibition resulted in the downregulation of glycolytic flux, ultimately suppressing lung cancer cell proliferation. Notably, triclabendazole reduced PKM2 acetylation by promoting the interaction between PKM2 and histone deacetylase 6 (HDAC6), thus blocking PKM2 nuclear localization. Moreover, we also demonstrated that triclabendazole-mediated inhibition of cell proliferation is driven by the downregulation of glycolysis, which enhanced AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling. Consistently, triclabendazole administration significantly inhibited tumor growth in vivo, correlating with the blockade of PKM2 nuclear translocation and lactate production decreased. Conclusion Our findings revealed that triclabendazole inhibits PKM2 nuclear localization and glycolysis through an HDAC6-dependent mechanism, leading to the activation of AMPK/mTOR signaling and suppression of lung cancer cell proliferation. These results suggested that triclabendazole holds promise as a potential therapeutic agent, with the HDAC6-PKM2 axis representing a novel target for lung cancer treatment.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acetylation / Acetylation - drug effects / AMP-activated protein kinase / AMP-Activated Protein Kinases - metabolism / Animals / Antibodies / Apoptosis / Benzimidazoles / Benzimidazoles - pharmacology / Benzimidazoles - therapeutic use / Bioengineering / Biomedical and Life Sciences / Biomedicine / Cancer therapies / Carcinogenesis - drug effects / Carcinogenesis - pathology / Carrier Proteins - metabolism / Cell culture / Cell growth / Cell Line, Tumor / Cell Nucleus - drug effects / Cell Nucleus - metabolism / Cell proliferation / Cell Proliferation - drug effects / Cholecystokinin / Deacetylation / Dehydrogenases / Down-regulation / Drug therapy / Enzymes / Flow cytometry / Gene regulation / Glucose metabolism / Glycolysis / Glycolysis - drug effects / HDAC6 / Health aspects / Histone deacetylase / Histone Deacetylase 6 - metabolism / Humans / Hydrolases / Kinases / Localization / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Medical research / Medicine/Public Health / Membrane Proteins - metabolism / Metabolism / Mice / Mice, Nude / Nuclear transport / Pharmacology, Experimental / Physiological aspects / PKM2 / Proliferation / Protein kinases / Protein Transport - drug effects / Proteins / Pyruvate kinase / Pyruvate Kinase - metabolism / Pyruvic acid / Rapamycin / Signal transduction / Signal Transduction - drug effects / Therapeutic applications / Thyroid Hormone-Binding Proteins / Thyroid Hormones - metabolism / TOR protein / TOR Serine-Threonine Kinases - metabolism / Translational Cancer Biology / Triclabendazole / Tumorigenesis