Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Molecular and Cell Biology, Taiwan International Graduate Program and National Defense Medical Center, Taipei, Taiwan.
Nat Commun. 2024 Oct 14;15(1):8844. doi: 10.1038/s41467-024-53139-y.
Vinca alkaloids, a class of tubulin-binding agent, are widely used in treating cancer, yet the emerging resistance compromises their efficacy. Hepatoma up-regulated protein (HURP), a microtubule-associated protein displaying heightened expression across various cancer types, reduces cancer cells' sensitivity to vinca-alkaloid drugs upon overexpression. However, the molecular basis behind this drug resistance remains unknown. Here we discover a tubulin-binding domain within HURP, and establish its role in regulating microtubule growth. Cryo-EM analysis reveals interactions between HURP's tubulin-binding domain and the vinca domain on β-tubulin -- the site targeted by vinca alkaloid drugs. Importantly, HURP competes directly with vinorelbine, a vinca alkaloid-based chemotherapeutic agent, countering microtubule growth defects caused by vinorelbine both in vitro and in vivo. Our findings elucidate a mechanism driving drug resistance in HURP-overexpressing cancer cells and emphasize HURP tubulin-binding domain's role in mitotic spindle assembly. This underscores its potential as a therapeutic target to improve cancer treatment.
长春碱类生物碱是一类微管结合剂，广泛用于治疗癌症，但新兴的耐药性使其疗效受到影响。肝癌上调蛋白（HURP）是一种微管相关蛋白，在多种癌症类型中表达水平升高，在过表达时会降低癌细胞对长春碱类药物的敏感性。然而，这种耐药性的分子基础尚不清楚。在这里，我们发现 HURP 内存在一个微管结合域，并确定了它在调节微管生长中的作用。冷冻电镜分析揭示了 HURP 的微管结合域与β-微管上长春碱结构域之间的相互作用——这是长春碱类药物的靶点。重要的是，HURP 与长春碱类化疗药物长春瑞滨直接竞争，在体外和体内均能拮抗长春瑞滨引起的微管生长缺陷。我们的研究结果阐明了 HURP 过表达的癌细胞产生耐药性的机制，并强调了 HURP 微管结合域在有丝分裂纺锤体组装中的作用。这突显了其作为治疗靶点改善癌症治疗的潜力。
