Repression of NF-kappaB and activation of AP-1 enhance apoptosis in prostate cancer cells.
Repression of NF-kappaB and activation of AP-1 enhance apoptosis in prostate cancer cells.
复制标题
NF-κB 的抑制和 AP-1 的激活可增强前列腺癌细胞的凋亡。
DOI：
10.1002/ijc.24139
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发表时间：
2009-04-15
影响因子：
6.4
通讯作者：
Olumi, Aria F.
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoping;Huang, Xu;Olumi, Aria F.
肿瘤坏死因子（TNFα）和肿瘤坏死因子相关凋亡配体（TRAIL）是肿瘤坏死因子家族的两个成员，它们通过许多共同的信号通路诱导细胞凋亡。虽然许多癌细胞对这些促凋亡剂敏感，但有些会产生耐药性。最近，我们已经证明，上调c-Fos/AP-1是必要的，但不足以使癌细胞进行TRAIL诱导的凋亡。在这里，我们提出了一个前列腺癌模型与不同的敏感性TNFα和TRAIL。我们发现，抑制NF-κB或激活AP-1只能部分地使耐药前列腺癌细胞对TNFα或TRAIL的促凋亡作用敏感。通过沉默TRAF 2、沉默RIP或IκB异位表达抑制NF-κB B部分致敏耐药前列腺癌类似地，c-Fos/AP-1的激活仅部分地使耐药癌细胞对TNFα或TRAIL的促凋亡作用敏感。然而，NF-κB的抑制和c-Fos/AP-1的激活可显著增强TNFα和TRAIL在耐药前列腺癌细胞中的促凋亡作用。因此，可能需要修改多个分子途径，以克服对促凋亡疗法有抗性的癌症。
TNFα and TRAIL, two members of the tumor necrosis factor family, share many common signalling pathways to induce apoptosis. Although many cancer cells are sensitive to these proapoptotic agents, some develop resistance. Recently we have demonstrated that up-regulation of c-Fos/AP-1 is necessary, but insufficient for cancer cells to undergo TRAIL-induced apoptosis. Here we present a prostate cancer model with differential sensitivity to TNFα and TRAIL. We show that inhibition of NF-κB or activation of AP-1 can only partially sensitize resistant prostate cancer cells to proapoptotic effects of TNFα or TRAIL. Inhibition of NF-κB by silencing TRAF2, by silencing RIP or by ectopic expression of IκB partially sensitized resistant prostate cancer. Similarly, activation of c-Fos/AP-1 only partially sensitized resistant cancer cells to proapoptotic effects of TNFα or TRAIL. However, concomitant repression of NF-κB and activation of c-Fos/AP-1 significantly enhanced the proapoptotic effects of TNFα and TRAIL in resistant prostate cancer cells. Therefore, multiple molecular pathways may need to be modified, in order to overcome cancers that are resistant to proapoptotic therapies.
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