PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2
PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2
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DOI：
10.1038/sj.onc.1206842
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发表时间：
2003-08-21
期刊：
影响因子：
8
通讯作者：
Schmid, RA
中科院分区：
文献类型：
--
作者：
Frese, S;Pirnia, F;Schmid, RA
肿瘤坏死因子相关凋亡诱导配体（Apo 2L/TRAIL）属于程序性细胞死亡诱导细胞因子家族。Apo 2L/TRAIL在多种肿瘤细胞中诱导凋亡。对Apo 2L/TRAIL诱导的细胞凋亡具有抗性的肿瘤细胞可以通过未知的机制被化疗药物和其他药剂敏化。在这里，我们报告PG 490（雷公藤内酯醇），一种从中国草药雷公藤提取的二萜三氧化物，并用于传统中药，敏感肺癌，但不是正常人支气管上皮细胞Apo 2L/TRAIL诱导的凋亡。致敏伴随着caspase-3和caspase-8的激活，而没有观察到caspase-9的裂解。通过流式细胞术测定细胞表面受体表明，在耐药细胞和致敏细胞之间，Apo 2L/TRAIL-R1和-R2表达无差异，这两种受体具有功能性死亡结构域。在用Apo 2L/TRAIL和PG 490的组合处理的细胞中，我们观察到ERK 2的活化，ERK 2是促分裂原活化蛋白激酶家族的成员。此外，ERK抑制剂U 0126可阻断致敏作用，而p38抑制剂SB 203580则不能阻断致敏作用，这表明这种作用需要ERK 2的激活。此外，在来自四名接受手术的患者的肺癌组织的离体培养物中也观察到肺癌细胞的致敏性。免疫组织化学染色显示，在用Apo 2L/TRAIL和PG 490处理的组织中增殖细胞核抗原（PCNA）明显减少。总之，通过Apo 2L/TRAIL和PG 490的组合诱导的细胞凋亡作为治疗肺癌的潜在新策略值得进一步评估。
Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to the family of programmed cell death-inducing cytokines. Apo2L/TRAIL induces apoptosis in a wide variety of tumor cells. Tumor cells that are resistant to Apo2L/TRAIL-induced apoptosis can be sensitized by chemotherapeutic drugs and other agents via an unknown mechanism. Here we report that PG490 (triptolide), a diterpene triepoxide extracted from the Chinese herb Tripterygium wilfordii and used in traditional Chinese medicine, sensitizes lung cancer but not normal human bronchial epithelial cells to Apo2L/TRAIL-induced apoptosis. Sensitization was accompanied by caspase-3 and caspase-8 activation, whereas no cleavage of caspase-9 was observed. Determination of cell surface receptors by flow cytometry demonstrated no difference in Apo2L/TRAIL-R1 and -R2 expression, the two receptors with functional death domains, between resistant and sensitized cells. In cells treated with the combination of Apo2L/TRAIL and PG490, we observed activation of ERK2, a member of the mitogen-activated protein kinase family. Furthermore, sensitization could be blocked by the ERK inhibitor U0126 but not the p38 inhibitor SB203580, suggesting that activation of ERK2 is required for this effect. In addition, sensitization of lung cancer cells was also seen in ex vivo culture of lung cancer tissue from four patients who underwent surgery. Immunohistochemical staining showed a clear reduction in proliferation cell nuclear antigen (PCNA) in tissue treated with Apo2L/TRAIL and PG490. In conclusion, apoptosis induced by the combination of Apo2L/TRAIL and PG490 warrants further evaluation as a potential new strategy for the treatment of lung cancer.