The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma cells
The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma cells
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DOI：
10.3892/ijo.2015.3307
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发表时间：
2016-03-01
影响因子：
5.2
通讯作者：
Giuliano, Michela
中科院分区：
文献类型：
--
作者：
Notaro, Antonietta;Sabella, Selenia;Giuliano, Michela
酸性和富含半胱氨酸的分泌蛋白（SPARC）是一种调节细胞-细胞和细胞-基质相互作用的多功能蛋白。在癌细胞中，SPARC在许多肿瘤中作为肿瘤启动子，但它也可以作为肿瘤抑制因子。我们之前的研究结果表明，合成大麻素win55,222 -2 （WIN）是一种有效的大麻素受体激动剂，能够使MG63骨肉瘤细胞对tnf相关凋亡诱导配体（TRAIL）诱导的凋亡敏感，并伴有内质网（ER）应激诱导和自噬标志物的增加。在本研究中，我们研究了SPARC在WIN/ trail诱导的细胞凋亡中的作用，结果表明，WIN以时间依赖性的方式增加了SPARC蛋白和mRNA的水平。RNA干扰分析表明，这一事件与WIN/ trail依赖性细胞凋亡有关，表明sparc沉默细胞对联合治疗诱导的细胞毒性作用不太敏感。我们的实验还表明，SPARC与caspase-8相互作用，从而可能有利于其转运到质膜和激活外源性凋亡途径。总之，据我们所知，我们的研究结果首次表明，win依赖性的SPARC水平升高在骨肉瘤细胞对TRAIL作用的敏感化中起着关键作用。
Secreted protein acidic and rich in cysteine (SPARC) is a multi-functional protein which modulates cell-cell and cell-matrix interactions. In cancer cells, SPARC behaves as a tumor promoter in a number of tumors, but it can also act as a tumor suppressor factor. Our previous results showed that the synthetic cannabinoid WIN55,212-2 (WIN), a potent cannabinoid receptor agonist, is able to sensitize osteosarcoma MG63 cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis which is accompanied with endoplasmic reticulum (ER)-stress induction and the increase in autophagic markers. In the present investigation, we studied the role of SPARC in WIN/TRAIL-induced apoptosis demonstrating that WIN increased the level of SPARC protein and mRNA in a time-dependent manner. This event was functional to WIN/TRAIL-dependent apoptosis as demonstrated by RNA interfering analysis which indicated that SPARC-silenced cells were less sensitive to cytotoxic effects induced by the combined treatment. Our experiments also demonstrate that SPARC interacts with caspase-8 thus probably favoring its translocation to plasma membrane and the activation of extrinsic apoptotic pathway. In conclusion, to the best of our knowledge, our results are the first to show that WIN-dependent increase in the level of SPARC plays a critical role in sensitizing osteosarcoma cells to TRAIL action.