Cytoprotective role of autophagy during paclitaxel-induced apoptosis in Saos-2 osteosarcoma cells
Cytoprotective role of autophagy during paclitaxel-induced apoptosis in Saos-2 osteosarcoma cells
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DOI：
10.3892/ijo.2013.1884
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发表时间：
2013-06-01
影响因子：
5.2
通讯作者：
Kim, Jong-Min
中科院分区：
文献类型：
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作者：
Kim, Hyeon Jun;Lee, Seung Gee;Kim, Jong-Min
骨肉瘤（OS）是儿童和青少年中最常见的原发性恶性骨癌。尽管紫杉醇 (PCX) 被认为是最重要的癌症化疗药物之一，但目前的 OS 治疗方案并未纳入该药物。因此，本研究的目的是评估PCX暴露后OS细胞的细胞死亡诱导情况，确定PCX激活的细胞死亡机制，并研究自噬是否与PCX诱导的细胞凋亡相关。本研究结果证实，暴露于低浓度PCX可诱导Saos-2细胞凋亡；此外，还观察到 caspase-3 激活、PARP 降解和 XIAP 下调与 PCX 诱导的细胞凋亡相结合。通过线粒体膜电位的改变（去极化）证实了线粒体事件（内在凋亡途径）在 PCX 诱导的 OS 细胞凋亡中的潜在参与。此外，用自噬特异性抑制剂 3-甲基腺嘌呤 (3-MA) 进行预处理，可显着增加 PCX 诱导的 Saos-2 细胞凋亡。 3-MA 对 PCX 诱导的细胞凋亡的增强伴随着线粒体中细胞色素 c 释放的增加、caspase-3 活性和 XIAP 下调，这表明抑制自噬通过激发 caspase-3 激活进一步刺激 PCX 诱导的线粒体相关（内在）细胞凋亡途径。因此，在 PCX 诱导的 Saos-2 OS 细胞凋亡过程中观察到的自噬代表了细胞稳态过程中细胞保护的作用。总之，本研究的结果表明，PCX 暴露可通过与线粒体介导的 caspase 依赖性途径相关的细胞凋亡有效诱导 OS 细胞死亡。 PCX 可以增加自噬活性，抑制自噬会增强 PCX 诱导的 OS 细胞凋亡。因此，有人认为，低剂量 PCX 疗法和自噬抑制剂疗法的联合治疗可能是在不久的将来改善 OS 化疗的有效且有效的策略。
Osteosarcoma (OS) is the most common primary malignant bone cancer in children and adolescents. Although paclitaxel (PCX) has been considered one of the most important cancer chemotherapeutic drugs, the current protocols for OS treatment do not incorporate this agent. Therefore, the purpose of this study was to evaluate the induction of cell death in OS cells after exposure to PCX, to identify the cell death mechanism(s) activated by PCX and to investigate whether autophagy is associated with PCX-induced apoptosis. The results of the present study confirmed that exposure to low PCX concentrations can induce apoptotic cell death in Saos-2 cells; furthermore, caspase-3 activation, PARP degradation and XIAP downregulation were observed in combination with PCX-induced apoptosis. The potential involvement of mitochondrial events (intrinsic apoptotic pathway) in PCX-induced apoptosis in OS cells was verified by the alteration (depolarization) of mitochondrial membrane potential. In addition, pretreatment with 3-methyladenine (3-MA), a specific inhibitor of autophagy, significantly increased PCX-induced apoptotic cell death in Saos-2 cells. The augmentation of PCX-induced apoptosis by 3-MA was accompanied by increase in the cytochrome c release from the mitochondria, caspase-3 activity and XIAP downregulation, which suggests that inhibiting autophagy further stimulates the PCX-induced mitochondrion-related (intrinsic) apoptotic pathway by provoking caspase-3 activation. Thus, autophagy observed during PCX-induced apoptosis in Saos-2 OS cells represents the role of cytoprotection in cellular homeostatic processes. In conclusion, the results of this study revealed that PCX exposure effectively induces OS cell death by apoptosis associated with the mitochondrial-mediated caspase-dependent pathway. PCX can increase autophagic activity and suppressing autophagy enhances PCX-induced apoptosis in OS cells. Therefore, it is suggested that combination treatment involving low-dose PCX therapy and autophagy inhibitor therapy could be an effective and potent strategy for improved chemotherapy for OS in the near future.