Yan Liang, Sun Yong, Shi Shan-Shan, Li Yuan, Zhang Yi-Fan, Qu Liang-Zhuo, Liu Jing, Dai Yong, Zha Qing-Bing, Fan Jun
Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, 517000, China.
Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510632, China.
J Transl Med. 2025 Sep 24;23(1):1001. doi: 10.1186/s12967-025-06905-5.
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.
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.
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.
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.
代谢重编程是癌细胞的一个标志，使其能够满足快速生长和增殖所需的更高能量和生物合成需求。最近，代谢酶的非经典功能在癌症研究中受到了广泛关注。丙酮酸激酶2（PKM2）已被确定为细胞核内转录调控的关键因子，为癌症治疗干预提供了新的机会。
在本研究中，用指示浓度的三氯苯达唑处理细胞（A549和H1299）。通过CCK8测定、集落形成测定、EdU染色和细胞计数测定来检测三氯苯达唑对增殖的影响。在裸鼠中进行肿瘤发生研究，以证明三氯苯达唑对肿瘤生长的抑制作用。利用PKM2核转位、HDAC6介导的去乙酰化、糖酵解通量下调以及AMPK/mTOR信号通路的激活来阐明三氯苯达唑在肺癌进展中的作用机制。
本研究发现，三氯苯达唑是一种常用于治疗肝片吸虫病的新型苯并咪唑衍生物，能有效抑制PKM2的核转位。这种抑制导致糖酵解通量下调，最终抑制肺癌细胞增殖。值得注意的是，三氯苯达唑通过促进PKM2与组蛋白去乙酰化酶6（HDAC6）之间的相互作用来降低PKM2的乙酰化，从而阻止PKM2的核定位。此外，我们还证明，三氯苯达唑介导的细胞增殖抑制是由糖酵解下调驱动的，这增强了AMP激活的蛋白激酶（AMPK）/雷帕霉素哺乳动物靶点（mTOR）信号。一致地，三氯苯达唑给药显著抑制体内肿瘤生长，这与PKM2核转位的阻断和乳酸产生的减少相关。
我们的研究结果表明，三氯苯达唑通过依赖HDAC6的机制抑制PKM2核定位和糖酵解，导致AMPK/mTOR信号激活并抑制肺癌细胞增殖。这些结果表明，三氯苯达唑有望成为一种潜在的治疗药物，HDAC6-PKM2轴代表了肺癌治疗的一个新靶点。
