Volatile anesthetics protect cancer cells against tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via caveolins.
Volatile anesthetics protect cancer cells against tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via caveolins.
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DOI：
10.1097/aln.0b013e3182276d42
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发表时间：
2011-09
期刊：
影响因子：
8.8
通讯作者：
Patel HH
中科院分区：
文献类型：
--
作者：
Kawaraguchi Y;Horikawa YT;Murphy AN;Murray F;Miyanohara A;Ali SS;Head BP;Patel PM;Roth DM;Patel HH
挥发性麻醉药对细胞存活的双重影响依赖于小窝蛋白的表达。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以及小窝蛋白-1(Cav-1)对其的调节作用。作者将人结肠癌细胞系暴露在异氟醚和促凋亡刺激下，并评估了Cav-1在细胞保护中的作用。他们通过核小体碎裂、caspase3的裂解表达和caspase活性的测定来评估细胞凋亡。为了测试这一机制，他们使用了药物抑制剂(即百日咳毒素)，并评估了糖酵解的变化。异氟烷(空气中1.2%)可促进HT29细胞(与对照组相比，P<；0.001)的凋亡率，而HCT116细胞(与对照组相比，P<；0.001)细胞凋亡率降低23%。在HCT116细胞中敲除Cav-1基因增加了对凋亡刺激的敏感性，但干扰小干扰RNA处理的细胞对凋亡刺激的敏感性增加(分别为19.7±0.4vs.20.0±0.6，P=0.7786和19.7±0.5vs.16.3±0.4，P=0.0012，异氟醚vs.对照)。经双因素方差分析，不同暴露时间的异氟醚对高表达Cav-1的HT29细胞的保护作用增强(P<；0.001)。百日咳毒素可有效阻断异氟醚对所有细胞株的抗凋亡作用。在异氟醚作用下，CAV-1细胞的糖酵解增加；然而，在肿瘤坏死因子相关的凋亡诱导配体存在的情况下，这种糖酵解的增加在HT29-Cav-1细胞中保持不变，而不是对照细胞。短暂的异氟醚暴露通过Cav-1依赖的机制导致对细胞凋亡的抵抗。
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). 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. 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. Brief isoflurane exposure leads to resistance against apoptosis via a Cav-1–dependent mechanism.