Inhibition of constitutive NF-κB activity by IκBαM suppresses tumorigenesis
Inhibition of constitutive NF-κB activity by IκBαM suppresses tumorigenesis
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DOI：
10.1038/sj.onc.1206323
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发表时间：
2003-03-06
期刊：
影响因子：
8
通讯作者：
Chiao, PJ
中科院分区：
文献类型：
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作者：
Fujioka, S;Sclabas, GM;Chiao, PJ
我们已经证明核因子-kappaB(NF-kappaB)在人胰腺癌和人胰腺癌细胞系中被结构性激活，但在正常胰腺组织和永生化的非致癌胰腺上皮细胞中不被激活，提示核因子-kappaB在胰腺癌的发生发展中起关键作用。为了阐明结构性的核因子-kappaB活性在人胰腺癌细胞中的作用，我们建立了表达磷酸化缺陷的IkappaBalpha(S32，36A)(IkappaBalphaM)的胰腺肿瘤细胞系，该细胞株可以阻断核因子-kappaB的活性。在这项研究中，我们发现，通过表达IkappaBalphaM来抑制结构性的NF-kappaB活性，可以抑制非转移性人胰腺癌细胞系PANC-1在裸鼠原位模型中的致瘤性。免疫组织化学分析显示，PANC-1来源的肿瘤表达血管内皮生长因子(VEGF)并诱导血管生成。通过表达licBaM抑制NF-kappaB信号转导可显著降低Bclx(L)和Bcl2的表达。细胞因子诱导的PANC-1细胞中血管内皮生长因子和白介素8的表达也减少。综上所述，这些结果提示，抑制核因子-kappaB信号通路可以抑制胰腺癌细胞的发生，提示核因子-kappaB信号通路是抗癌药物的潜在靶点。
We have demonstrated that nuclear factor-kappaB (NF-kappaB) is constitutively activated in human pancreatic adenocarcinoma and human pancreatic cancer cell lines but not in normal pancreatic tissues or in immortalized, nontumorigenic pancreatic epithelial cells, suggesting that NF-kappaB plays a critical role in the development of pancreatic adenocarcinoma. To elucidate the role of constitutive NF- kappaB activity in human pancreatic cancer cells, we generated pancreatic tumor cell lines that express a phosphorylation defective IkappaBalpha (S32, 36A) (IkappaBalphaM) that blocks NF-kappaB, activity. In this study, we showed that inhibiting constitutive NF-kappaB activity by expressing IkappaBalphaM suppressed the tumorigenicity of a nonmetastatic human pancreatic cancer cell line, PANC-1, in an orthotopic nude mouse model. Immunohistochemical analysis showed that PANC-1-derived tumors expressed vascular endothelial growth factor (VEGF) and induced angiogenesis. Inhibiting NF-kappaB signaling by expressing licBaM significantly reduced expression of Bcl-x(L) and Bcl-2. The cytokine-induced expression of VEGF and Interleukin-8 in PANC-1 cells is also decreased. Taken together, these results suggest that the inhibition of NF-kappaB signaling can suppress tumorigenesis of pancreatic cancer cells and that the NF-kappaB signaling pathway is a potential target for anticancer agents.