Inhibiting proliferation and enhancing chemosensitivity to taxanes in osteosarcoma cells by RNA interference-mediated downregulation of Stathmin expression
Inhibiting proliferation and enhancing chemosensitivity to taxanes in osteosarcoma cells by RNA interference-mediated downregulation of Stathmin expression
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DOI：
10.2119/2007-00046.wang
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发表时间：
2007-11-01
影响因子：
5.7
通讯作者：
Zhang, Hui-Zhong
中科院分区：
文献类型：
--
作者：
Wang, Rui;Dong, Ke;Zhang, Hui-Zhong
Stathmin（Oncoprotein 18）是一种信号转导调节因子，在细胞分裂和恶性肿瘤的发生发展中起重要作用。Stothmin是一种普遍存在于细胞内的磷蛋白，在多种人类恶性肿瘤（包括骨肉瘤）中过表达。为了研究stothmin作为人骨肉瘤治疗靶点的潜在用途，我们采用RNA干扰（小干扰RNA（siRNA））来降低stothmin在人骨肉瘤细胞系中的表达，并分析其表型变化。结果表明，下调stothmin基因在人骨肉瘤细胞中的表达可显著抑制骨肉瘤细胞的体外增殖和体内致瘤性。特异性下调诱导细胞停滞在细胞周期的G（2）/M期，并最终导致细胞凋亡，细胞死亡。紫杉烷类是一组有效的化疗药物，其活性通过稳定有丝分裂纺锤体的微管来介导。在本研究中，我们还观察到通过联合使用紫杉烷类和RNA干扰介导的stathmin下调的细胞毒性效应的协同增强。所有这些实验数据表明，stathmin下调可以导致有效的抗肿瘤活性和紫杉烷类药物在人骨肉瘤中的化学增敏活性。
Stathmin (Oncoprotein 18), a signal transduction regulatory factor, plays an important role in cell division and malignant tumor development. Stothmin is a ubiquitous intracellular phosphoprotein that is overexpressed in a variety of human malignancies, including osteosarcoma. To investigate the potential use of stothmin as a therapeutic target for human osteosarcomas, we employed RNA interference (small interfering RNA (siRNA)) to reduce stathmin expression in human osteosarcoma cell lines and analyzed their phenotypic changes. Results showed that the downregulation of stothmin expression in human osteosarcoma cells significantly inhibited cell proliferation in vitro and tumorigenicity in vivo. The specific downregulation induced cell arrest in the G(2)/M phase of cell cycle and eventually apoptotic,cell death. Taxanes are a group of effective chemotherapeutic agents whose activity is mediated through stabilization of the microtubules of the mitotic spindle. In the present study, we also observed a synergistic enhancement of the cytotoxicity effect by combination use of taxanes and RNA interference-mediated stathmin downregulation. All these experimental data indicate that stathmin downregulation can lead to potent antitumor activity and chemosensitizing activity to taxanes in human osteosarcomas.