Department of Orthopaedics, The First Hospital of Nanchang, Nanchang, China.
Department of Breast Cancer Surgery, Jiangxi Provincial Cancer Hospital, Nanchang, China.
Clin Exp Pharmacol Physiol. 2022 Mar;49(3):380-390. doi: 10.1111/1440-1681.13613. Epub 2021 Nov 30.
Despite recent advances in diagnosis and treatment, osteosarcoma remains as the most common bone cancer in children and is associated with poor prognosis. Growing evidence has supported dysregulation of threonine and tyrosine protein kinase (TTK) expression as a hallmark of multiple cancers, however, its function in osteosarcoma remains to be elucidated. In the present study, we found that TTK was frequently overexpressed in osteosarcoma and associated with increased tumour growth and progression. Moreover, using both in vitro and in vivo assays, we provided evidence that TTK level was regulated by a molecular chaperone, heat shock protein 90 (Hsp90). Hsp90 directly interacted with TTK and prevents proteasome-dependent TTK degradation, leading to the accumulation of TTK in osteosarcoma cells. Elevated TTK promoted cancer cell proliferation and survival by activating cell-cycle progression and inhibiting apoptosis. Consistently, depletion of TTK by Hsp90 inhibition induced cell-cycle arrest, generated aneuploidy and eventually resulted in apoptotic cancer cell death. Together, our study revealed an important Hsp90-TTK regulatory axis in osteosarcoma cells to promote cancer cell growth and survival. These findings expand our knowledge on osteosarcoma pathogenesis and offer novel therapeutic options for clinical practice.
尽管在诊断和治疗方面取得了一些进展，但骨肉瘤仍然是儿童中最常见的骨癌，预后不良。越来越多的证据表明，苏氨酸和酪氨酸蛋白激酶（TTK）表达失调是多种癌症的标志，然而，其在骨肉瘤中的功能仍有待阐明。在本研究中，我们发现 TTK 在骨肉瘤中经常过表达，并与肿瘤生长和进展增加有关。此外，通过体外和体内实验，我们提供了证据表明分子伴侣热休克蛋白 90（Hsp90）调节 TTK 水平。Hsp90 与 TTK 直接相互作用，防止蛋白酶体依赖的 TTK 降解，导致 TTK 在骨肉瘤细胞中的积累。升高的 TTK 通过激活细胞周期进程和抑制细胞凋亡促进癌细胞增殖和存活。一致地，通过 Hsp90 抑制耗尽 TTK 诱导细胞周期停滞，产生非整倍体，最终导致癌细胞凋亡死亡。总之，我们的研究揭示了骨肉瘤细胞中重要的 Hsp90-TTK 调节轴，以促进癌细胞的生长和存活。这些发现扩展了我们对骨肉瘤发病机制的认识，并为临床实践提供了新的治疗选择。
