挥发性麻醉剂通过窖蛋白保护癌细胞免受肿瘤坏死因子相关凋亡诱导配体诱导的细胞凋亡。
Volatile anesthetics protect cancer cells against tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via caveolins.
机构信息
Department of Anesthesiology, University of California, San Diego, La Jolla, California, USA.
出版信息
Anesthesiology. 2011 Sep;115(3):499-508. doi: 10.1097/ALN.0b013e3182276d42.
BACKGROUND
Volatile anesthetics have a dual effect on cell survival dependent on caveolin expression. The effect of volatile anesthetics on cancer cell survival and death after anesthetic exposure has not been well investigated. The authors examined the effects of isoflurane exposure on apoptosis and its regulation by caveolin-1 (Cav-1).
METHODS
The authors exposed human colon cancer cell lines to isoflurane and proapoptotic stimuli and assessed what role Cav-1 plays in cell protection. They evaluated apoptosis using assays for nucleosomal fragmentation, cleaved caspase 3 expression, and caspase activity assays. To test the mechanism, they used pharmacologic inhibitors (i.e., pertussis toxin) and assessed changes in glycolysis.
RESULTS
Apoptosis as measured by nucleosomal fragmentation was enhanced by isoflurane (1.2% in air) in HT29 (by 64% relative to control, P < 0.001) and decreased in HCT116 (by 23% relative to control, P < 0.001) cells. Knockdown of Cav-1 in HCT116 cells increased the sensitivity to apoptotic stimuli but not with scrambled small interfering RNA (siRNA) treatment (19.7 ± 0.4 vs. 20.0 ± 0.6, P = 0.7786 and 19.7 ± 0.5 vs. 16.3 ± 0.4, P = 0.0012, isoflurane vs. control in Cav-1 small interfering RNA vs. scrambled small interfering RNA treated cells, respectively). The protective effect of isoflurane with various exposure times on apoptosis was enhanced in HT29 cells overexpressing Cav-1 (P < 0.001 by two-way ANOVA). Pertussis toxin effectively blocked the antiapoptotic effect of isoflurane exhibited by Cav-1 in all cell lines. Cav-1 cells had increased glycolysis with isoflurane exposure; however, in the presence of tumor necrosis factor-related apoptosis-inducing ligand, this increase in glycolysis was maintained in HT29-Cav-1 but not control cells.
CONCLUSION
Brief isoflurane exposure leads to resistance against apoptosis via a Cav-1-dependent mechanism.
背景
挥发性麻醉剂对细胞存活有双重影响，这取决于窖蛋白的表达。挥发性麻醉剂对麻醉暴露后癌细胞存活和死亡的影响尚未得到很好的研究。作者研究了异氟醚暴露对细胞凋亡的影响及其对窖蛋白-1（Cav-1）的调节作用。
方法
作者使人类结肠癌细胞系暴露于异氟醚和促凋亡刺激物，并评估 Cav-1 在细胞保护中的作用。他们使用核小体片段化、切割 caspase 3 表达和 caspase 活性测定来评估细胞凋亡。为了测试机制，他们使用了药理学抑制剂（即百日咳毒素），并评估了糖酵解的变化。
结果
异氟醚（空气中 1.2%）增强了 HT29 细胞（与对照相比增加了 64%，P<0.001）的核小体片段化所测凋亡，而降低了 HCT116 细胞（与对照相比减少了 23%，P<0.001）的凋亡。在 HCT116 细胞中敲低 Cav-1 增加了对凋亡刺激的敏感性，但用对照小干扰 RNA（siRNA）处理则没有（分别用异氟醚处理 Cav-1 小干扰 RNA 转染细胞与对照小干扰 RNA 转染细胞时为 19.7±0.4 对 20.0±0.6，P=0.7786 和 19.7±0.5 对 16.3±0.4，P=0.0012）。用 Cav-1 过表达增强了 HT29 细胞中异氟醚对凋亡的保护作用，在各种暴露时间下（通过双因素方差分析，P<0.001）。百日咳毒素在所有细胞系中有效阻断了 Cav-1 表现出的异氟醚的抗凋亡作用。Cav-1 细胞在暴露于异氟醚时糖酵解增加；然而，在肿瘤坏死因子相关凋亡诱导配体存在的情况下，这种糖酵解的增加在 HT29-Cav-1 细胞中得以维持，但在对照细胞中则没有。
结论
短暂的异氟醚暴露通过 Cav-1 依赖性机制导致抗凋亡。
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