A signal network involving coactivated NF-κB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas
A signal network involving coactivated NF-κB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas
复制标题
DOI：
10.1002/ijc.23324
复制
发表时间：
2008-05-01
影响因子：
6.4
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Lee, Tin Lap;Yeh, Jason;Chen, Zhong
消除细胞凋亡以维持细胞存活是癌症发展过程中必不可少的一步。信号转录因子NF-kappa B或STAT3的异常激活、P53状态的改变或bc1/bax家族的表达都被报道影响包括头颈部鳞状细胞癌(HNSCC)在内的癌症的细胞生存。然而，对这些改变进行单独的分子靶向研究却产生了令人失望的结果。在我们的研究中，我们验证了一种假设，即涉及NF-kappa B、STAT3和P53的信号网络的变化调控促凋亡的Bax和抗凋亡的bclxl蛋白的表达，并促进HNSCC的细胞生存。我们发现，核因子-kappaB和STAT3共同激活，并在细胞因子刺激或siRNA下调的情况下，两者都调节bax/bclxl。低wt p5 3蛋白表达的HNSCC细胞株较高表达mt p5 3蛋白的HNSCC细胞株之间的调控作用更强，提示p5 3蛋白表达降低可能增强了核转录因子-kappaB、STAT3和bclxl的活性。Wt p53的重新表达抑制了核转录因子-kappaB和STAT3的核结合活性，抑制了bc1-xl的表达，而诱导了p21和bax的表达。P53的过度表达和核因子-kappaB或STAT3的抑制分别诱导了bax/bclxl比值的升高和细胞的凋亡。相反，核因子-kappaB或STAT3诱导的细胞因子降低了bax/bclxl比值。因此，涉及信号共激活的NF-kappa B和STAT3的网络，通过p53失活或突变进行不同的修饰，促进了HNSCC中bax/bclxl的表达变化和细胞存活。抑制NF-kappaB和STAT3的信号激活以及p53的重新表达可能是恢复bax/bclxl调节和HNSCC细胞毒治疗的最有效策略。(C)2008年Wiley-Liss，Inc.
Abrogation of apoptosis to sustain cell survival is an essential step in development of cancer. Aberrant activation of signal transcription factors NF-kappa B or STAT3, alterations in p53 status, or BCL/BAX family expression have each been reported to affect cell survival in cancer, including head and neck squamous cell carcinomas (HNSCC). However, molecular targeting of these alterations individually has yielded disappointing results. In our study, we examined the hypothesis that alterations in a signal network involving NF-kappa B, STAT3 and p53 modulates expression of proapoptotic BAX and antiapoptotic BCL-XL proteins, and promotes cell survival of HNSCC. We found that NF-kappa B and STAT3 are coactivated together, and with cytokine stimulation or siRNA knock-down, both modulate BAX/BCL-XL. Greater modulation among HNSCC lines expressing low wt p53 than those over-expressing mt p53 protein suggested that decreased p53 expression might enhance activation of NF-kappa B, STAT3 and BCL-XL. Reexpression of wt p53 suppressed NF-kappa B and STAT3 nuclear binding activity, and BCL-XL expression, while inducing p21 and BAX. Over-expression of p53 together with inhibition of NF-kappa B or STAT3 induced greater increase in the BAX/BCL-XL ratio and apoptosis than modulation of these transcription factors individually. Conversely, NF-kappa B or STAT3 inducing cytokines decreased the BAX/BCL-XL ratio. Thus, a network involving signal coactivation of NF-kappa B and STAT3, differentially modified by p53 inactivation or mutation, promotes altered BAX/BCL-XL expression and cell survival in HNSCC. Inhibition of signal activation of both NF-kappa B and STAT3 together with reexpression of p53 could be the most effective strategy to restore BAX/BCL-XL regulation and for cytotoxic therapy of HNSCC. (C) 2008 Wiley-Liss, Inc.