Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB.
Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB.
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发表时间：
2004
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通讯作者：
Ajoy K. Samanta;Helen J Huang;Robert C. Bast;Warren S-L Liao
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作者：
Ajoy K. Samanta;Helen J Huang;Robert C. Bast;Warren S-L Liao
许多癌症都有组成性激活NFkappaB，其升高有助于癌细胞抵抗化疗药物诱导的细胞凋亡。虽然有研究表明丝裂原活化蛋白激酶/细胞外调节激酶激酶激酶激酶3 （MEKK3）参与NFkappaB的活化，但其与细胞凋亡和癌症的关系尚不清楚。在这项研究中，我们建立了细胞模型系统来研究MEKK3的稳定表达是否会导致NFkappaB活性增加并赋予细胞凋亡抗性。此外，我们在乳腺癌和卵巢癌中研究了MEKK3表达是否可能改变并与NFkappaB活性异常相关。我们发现，过表达MEKK3的稳定细胞系不仅具有更高水平的NFkappaB结合活性，而且对细胞因子刺激更敏感。这些稳定的细胞Bcl-2和xIAP的基础表达量比亲本细胞高2-4倍。与细胞存活基因的表达增加一致，MEKK3稳定的细胞显示caspase 3和8的激活以及聚（adp -核糖）聚合酶切割的活性降低，并且对肿瘤坏死因子相关的凋亡诱导配体、阿霉素、柔红霉素、喜树碱和紫杉醇诱导的凋亡的抗性显著增强。有趣的是，对人类乳腺癌和卵巢癌的分析表明，这些样本中有很大一部分MEKK3蛋白水平升高，NFkappaB结合活性相应增加。因此，我们的研究结果表明，MEKK3的表达升高似乎在乳腺癌和卵巢癌中经常发生，并且细胞中MEKK3的过表达导致NFkappaB活性增加和细胞存活因子表达增加，最终有助于细胞抵抗凋亡。因此，MEKK3可以作为一个治疗靶点来控制癌细胞对细胞因子或药物诱导的细胞凋亡的抵抗。
Many cancers have constitutively activated NFkappaB, the elevation of which contributes to cancer cell resistance to chemotherapeutic agent-induced apoptosis. Although mitogen-activated protein kinase/extracellular-regulated kinase kinase kinase-3 (MEKK3) has been shown to participate in the activation of NFkappaB, its relations to apoptosis and cancer are unclear. In this study, we established cell model systems to examine whether stable expression of MEKK3 could lead to increased NFkappaB activity and confer resistance to apoptosis. In addition, we investigated in breast and ovarian cancers whether MEKK3 expression may be altered and correlated with aberrant NFkappaB activity. We show that stable cell lines overexpressing MEKK3 not only had elevated levels of NFkappaB binding activity but also were more responsive to cytokine stimulation. These stable cells showed 2-4-fold higher basal expression of Bcl-2 and xIAP than the parental cells. Consistent with this increased expression of cell survival genes, MEKK3 stable cells showed reduced activation of caspases 3 and 8 and poly(ADP-ribose) polymerase cleavage and dramatically increased resistance to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand, doxorubicin, daunorubicin, camptothecin, and paclitaxel. Intriguingly, analysis of human breast and ovarian cancers showed that a significant fraction of these samples have elevated MEKK3 protein levels with corresponding increases in NFkappaB binding activities. Thus, our results established that elevated expression of MEKK3 appears to be a frequent occurrence in breast and ovarian cancers and that overexpression of MEKK3 in cells leads to increased NFkappaB activity and increased expression of cell survival factors and ultimately contributes to their resistance to apoptosis. As such, MEKK3 may serve as a therapeutic target to control cancer cell resistance to cytokine- or drug-induced apoptosis.