PIDDosome expression and the role of caspase-2 activation for chemotherapy-induced apoptosis in RCCs.
PIDDosome expression and the role of caspase-2 activation for chemotherapy-induced apoptosis in RCCs.
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DOI：
10.3233/clo-2009-0492
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Mahotka C
中科院分区：
文献类型：
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作者：
Heikaus S;Pejin I;Gabbert HE;Ramp U;Mahotka C
背景：caspase-2 激活对于介导癌症细胞凋亡的重要性尚不清楚，并且不同肿瘤类型之间似乎有所不同。此外，关于caspase-2（可以选择性剪接成caspase-2L和caspase-2S）以及其他PIDDosome成员PIDD和RAIDD在体内人类肿瘤中的表达，仅获得很少的数据。因此，我们研究了它们在体内透明细胞类型肾细胞癌（RCC）中的表达，并分析了 caspase-2 在体外化疗诱导的 RCC 细胞凋亡中的作用。 方法：通过半定量实时 PCR、Western Blot 和 Caspase-2 检测进行分析。 结果：我们的体内结果显示，在肿瘤进展过程中，由于 caspase-2S mRNA 在总 caspase-2 mRNA 表达中的相对份额增加，促凋亡 caspase-2L 表达总体下降。此外，可以观察到PIDD和RAIDD的表达增加。相比之下，抗凋亡 BCL-2 表达仅在肿瘤早期阶段增加，而在 pT3 RCC 中表达减少。在体外，RCC 细胞系中 caspase-2 的激活与肿瘤细胞对拓扑替康诱导的细胞凋亡的敏感性一致。然而，抑制 caspase-2 并不能阻止拓扑替康诱导的细胞凋亡。有趣的是，拓扑替康耐药性可以通过细胞凋亡敏感药物 HA14-1 来克服。 结论：我们的研究证实了肾细胞癌肿瘤进展过程中向更抗凋亡的转录环境转变的概念。此外，它表明 caspase-2 参与化疗诱导的 RCC 细胞凋亡，尽管这不是强制性的。此外，抑制抗凋亡 BCL-2 家族成员可能提供克服 RCC 化疗耐药性的可能方法。
Background: The importance of caspase-2 activation for mediating apoptosis in cancer is not clear and seems to differ between different tumour types. Furthermore, only few data have been obtained concerning the expression of caspase-2, which can be alternatively spliced into caspase-2L and caspase-2S, and the other PIDDosome members PIDD and RAIDD in human tumours in vivo. We, therefore, investigated their expression in renal cell carcinomas (RCCs) of the clear cell type in vivo and analysed the role of caspase-2 in chemotherapy-induced apoptosis in RCCs in vitro. Methods: The analyses were performed by semiquantitative real-time PCR, Western Blot and Caspase-2 Assay. Results: Our in vivo results showed an overall decrease in proapoptotic caspase-2L expression during tumour progression due to an increase in the relative share of caspase-2S mRNA in total caspase-2 mRNA expression. Furthermore, an increase in the expression of PIDD and RAIDD could be observed. In contrast, antiapoptotic BCL-2 expression increased only during early tumour stages, whereas expression decreased in pT3 RCCs. In vitro, caspase-2 activation in RCC cell lines coincidenced with sensitivity of tumour cells towards Topotecan-induced apoptosis. However, inhibition of caspase-2 could not prevent Topotecan-induced apoptosis. Interestingly, Topotecan-resistance could be overcome by the apoptosis-sensitizing drug HA14-1. Conclusions: Our study confirms the concept of a shift towards a more antiapoptotic transcriptional context during tumour progression in RCCs. Furthermore, it shows that caspase-2 participates in chemotherapy-induced apoptosis in RCCs although it is not mandatory for it. Additionally, inhibition of antiapoptotic BCL-2 family members might provide a possible way to overcome chemotherapy resistance of RCCs.