Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, 90095, USA.
Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
Cell Death Dis. 2018 May 1;9(5):446. doi: 10.1038/s41419-018-0474-4.
Synovial sarcoma is a highly aggressive but rare form of soft tissue malignancy that primarily affects the extremities of the arms or legs, for which current chemotherapeutic agents have not been proven to be very effective. The cyclin-dependent kinase 4/6-retinoblastoma protein (CDK4/6-Rb) pathway of cell cycle control is known to be aberrant in a large proportion of cancers. Recently, CDK4 inhibitors have successfully been used pre-clinically for the treatment of many human cancers, and in 2015, following the success of clinical trials, the FDA approved the first selective CDK4/6 inhibitor, palbociclib, for the treatment of endocrine therapy resistant breast cancers. However, the expression and therapeutic potential of targeting CDK4 in synovial sarcoma remains unclear. In the present study, we report that CDK4 is highly expressed in human synovial sarcoma, and high CDK4 expressions are associated with poor prognosis in sarcomas patients and the clinical stage and the TNM grade in synovial sarcoma patients. Knockdown of CDK4 with specific small interference RNAs inhibits cell proliferation and enhances apoptotic effects in synovial sarcoma cells. CDK4 inhibitor palbociclib suppresses synovial sarcoma cell proliferation and growth in a dose and time-dependent manner. Palbociclib also inhibits the CDK4/6-Rb signaling pathway and promotes cell apoptosis without changing CDK4/6 protein levels, suggesting that palbociclib only represses the hyper-activation, not the expression of CDK4/6. Flow cytometry analysis reveals that palbociclib induces G1 cell-cycle arrest and apoptotic effects by targeting the CDK4/6-Rb pathway in synovial sarcoma cells. Furthermore, wound healing assays demonstrate that inhibition of the CDK4/6-Rb pathway by palbociclib significantly decreases synovial sarcoma cell migration in vitro. Our study highlights the importance of the CDK4/6-Rb pathway in human synovial sarcoma pathogenesis, and the role of the current selective CDK4/6 inhibitor, palbociclib, as a potential promising targeted therapeutic agent in the treatment of human synovial sarcoma.
滑膜肉瘤是一种高度侵袭性但罕见的软组织恶性肿瘤，主要发生于手臂或腿部的四肢，目前的化疗药物已被证明对此类肿瘤效果不佳。细胞周期调控的细胞周期蛋白依赖性激酶 4/6-视网膜母细胞瘤蛋白（CDK4/6-Rb）途径在很大比例的癌症中存在异常。最近，CDK4 抑制剂已成功地在临床上用于治疗多种人类癌症，并且在 2015 年，在临床试验成功之后，FDA 批准了第一个选择性 CDK4/6 抑制剂 palbociclib，用于治疗内分泌治疗耐药的乳腺癌。然而，在滑膜肉瘤中靶向 CDK4 的表达和治疗潜力尚不清楚。在本研究中，我们报告 CDK4 在人类滑膜肉瘤中高度表达，并且 CDK4 的高表达与肉瘤患者的预后不良以及滑膜肉瘤患者的临床分期和 TNM 分级相关。特异性小干扰 RNA 敲低 CDK4 可抑制滑膜肉瘤细胞的增殖并增强其凋亡作用。CDK4 抑制剂 palbociclib 以剂量和时间依赖的方式抑制滑膜肉瘤细胞的增殖和生长。Palbociclib 还抑制 CDK4/6-Rb 信号通路并促进细胞凋亡，而不改变 CDK4/6 蛋白水平，这表明 palbociclib 仅抑制 CDK4/6 的过度激活，而不是其表达。流式细胞术分析显示，palbociclib 通过靶向 CDK4/6-Rb 通路诱导滑膜肉瘤细胞 G1 期细胞周期阻滞和凋亡作用。此外，划痕愈合实验表明 palbociclib 抑制 CDK4/6-Rb 通路可显著降低滑膜肉瘤细胞在体外的迁移能力。我们的研究强调了 CDK4/6-Rb 通路在人类滑膜肉瘤发病机制中的重要性，以及当前选择性 CDK4/6 抑制剂 palbociclib 作为治疗人类滑膜肉瘤的一种有前途的靶向治疗药物的作用。
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