c-Myc-dependent etoposide-induced apoptosis involves activation of Bax and caspases, and PKCdelta signaling
c-Myc-dependent etoposide-induced apoptosis involves activation of Bax and caspases, and PKCdelta signaling
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DOI：
10.1002/jcb.20816
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发表时间：
2006-08-15
影响因子：
4
通讯作者：
Henriksson, Marie
中科院分区：
文献类型：
--
作者：
Albihn, Ami;Loven, Jakob;Henriksson, Marie
c-Myc 转录因子是细胞增殖、分化和凋亡的关键调节因子。虽然 myc 的失调会诱导程序性细胞死亡，但细胞凋亡程序的缺陷会促进 Myc 驱动的肿瘤发展。我们用细胞毒性药物处理c-Myc诱导型小鼠细胞和具有不同c-myc状态的大鼠成纤维细胞，以探讨c-Myc对药物诱导的细胞凋亡的影响。我们发现 c-Myc 过表达增强了依托泊苷、阿霉素和顺铂诱导的小鼠成纤维细胞的细胞死亡。此外，这些药物在表达 c-Myc 的细胞中引发强烈的细胞凋亡反应，但在 c-myc 无效的 Rat1 细胞中引发微弱的细胞凋亡。相比之下，星形孢菌素诱导的细胞凋亡是不依赖于c-Myc的，证实了c-myc无效细胞中的功能性细胞凋亡途径。在依托泊苷和阿霉素治疗后，细胞凋亡与 c-Myc 依赖性 Bax 激活平行，但在顺铂给药后则不然。所有三种药物在 c-Myc 表达细胞中诱导的 caspase 激活高于 c-myc 无效细胞。此外，依托泊苷处理 c-Myc 表达细胞会导致 PKC δ 裂解，而抑制 PKC δ 会减少依托泊苷诱导的细胞凋亡并阻止 Bax 激活。综上所述，这些发现表明 Bax 和 caspase 激活以及 PKC delta 信号传导参与 c-Myc 依赖性依托泊苷诱导的细胞凋亡。
The c-Myc transcription factor is a key regulator of cell proliferation, differentiation, and apoptosis. While deregulation of myc induces programmed cell death, defects in the apoptotic program facilitate Myc-driven tumor development. We have treated c-Myc inducible mouse cells and rat fibroblasts with different c-myc status with cytotoxic drugs to explore the effect of c-Myc on drug-induced apoptosis. We found that c-Myc overexpression potentiated etoposide, doxorubicin-, and cisplatin-induced cell death in mouse fibroblasts. In addition, these drugs provoked a strong apoptotic response in c-Myc-expressing cells, but a weak apoptosis in c-myc null Rat1 cells. In contrast, staurosporine-induced apoptosis was c-Myc-independent, confirming a functional apoptotic pathway in c-myc null cells. Apoptosis was paralleled by c-Myc-dependent Bax-activation after etoposide and doxorubicin treatment, but not after cisplatin administration. All three drugs induced higher caspase activation in c-Myc expressing cells than in c-myc null cells. Furthermore, etoposide treatment of c-Myc expressing cells resulted in PKC delta cleavage, while inhibition of PKC delta reduced etoposide-induced apoptosis and prevented Bax activation. Taken together, these findings suggest that Bax and caspase activation, together with PKC delta signaling are involved in c-Myc-dependent etoposide-induced apoptosis.