Wang Zili, He Rongzhen, Xia Hansong, Wei Yu, Wu Song
Department of Orthopaedic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China.
Oncol Lett. 2017 May;13(5):3465-3470. doi: 10.3892/ol.2017.5941. Epub 2017 Mar 28.
Chemoresistance is a major cause for the poor prognosis of osteosarcoma (OS) patients. However, our understanding of mechanisms underlying chemoresistance in OS are limited. The present study aimed to investigate the effect of stathmin 1 (STMN1) on paclitaxel-induced chemoresistance, as well as the underlying mechanism. Western blot analysis data revealed that the expression level of STMN1 was dramatically increased in OS cell lines (HOS, Saos-2, U-2OS and MG-63), when compared to normal osteoblast hFOB1.19 cells. Furthermore, treatment with paclitaxel led to upregulation of STMN1 in U-2OS cells, accompanied by activation of autophagy, which may attenuate the cytotoxicity of paclitaxel in OS cells. Following knockdown of STMN1 expression, paclitaxel-induced autophagy was significantly reduced, accompanied by increased cytotoxicity of paclitaxel to U-2OS cells. In addition, blockade of mammalian target of rapamycin signaling attenuated the inhibitory effect of STMN1 knockdown on autophagy in OS cells. In conclusion, the present study demonstrated that knockdown of STMN1 enhances osteosarcoma cell chemosensitivity to paclitaxel through inhibition of autophagy. Therefore, STMN1 may be a potential target for the treatment of chemoresistant OS.
化疗耐药是骨肉瘤（OS）患者预后不良的主要原因。然而，我们对骨肉瘤化疗耐药潜在机制的了解有限。本研究旨在探讨14-3-3蛋白ζ（STMN1）对紫杉醇诱导的化疗耐药的影响及其潜在机制。蛋白质印迹分析数据显示，与正常成骨细胞hFOB1.19细胞相比，骨肉瘤细胞系（HOS、Saos-2、U-2OS和MG-63）中STMN1的表达水平显著升高。此外，紫杉醇处理导致U-2OS细胞中STMN1上调，同时伴有自噬激活，这可能减弱了紫杉醇对骨肉瘤细胞的细胞毒性。在敲低STMN1表达后，紫杉醇诱导的自噬显著降低，同时紫杉醇对U-2OS细胞的细胞毒性增加。此外，雷帕霉素靶蛋白信号通路的阻断减弱了STMN1敲低对骨肉瘤细胞自噬的抑制作用。总之，本研究表明，敲低STMN1可通过抑制自噬增强骨肉瘤细胞对紫杉醇的化学敏感性。因此，STMN1可能是治疗化疗耐药骨肉瘤的潜在靶点。
