Function of nuclear factor kappaB in pancreatic cancer metastasis.
Function of nuclear factor kappaB in pancreatic cancer metastasis.
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发表时间：
2003
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通讯作者：
S. Fujioka;G. Sclabas;C. Schmidt;W. Frederick;Q. Dong;J. Abbruzzese;Douglas B. Evans;C. Baker;P. Chiao
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作者：
S. Fujioka;G. Sclabas;C. Schmidt;W. Frederick;Q. Dong;J. Abbruzzese;Douglas B. Evans;C. Baker;P. Chiao
目的探讨组成型核因子κ B（NF κ B）活性在胰腺癌细胞中的作用。我们已经证明，转录因子NF κ B在人胰腺癌和人胰腺癌细胞系中被组成性激活，但在正常胰腺组织或永生化/非致瘤性胰腺上皮细胞中不被激活，这表明NF κ B在胰腺癌的发展中起着关键作用。实验设计通过在核因子-κ B磷酸化抑制剂突变体（IkappaBalphaM）逆转录病毒感染后合并所有嘌呤霉素抗性克隆，我们产生了表达阻断NF κ B活性的IkappaBalphaM（S32，36 A）的胰腺肿瘤细胞系。在原位裸鼠模型中测定转移表型的抑制。通过电泳迁移率变动分析测定NF κ B活性，并通过北方、西方和免疫组织化学分析来分析NF κ B下游靶基因的表达。结果我们发现，通过表达IkappaBalphaM抑制组成型NF κ B活性可抑制转移性人胰腺癌细胞系AsPc-1在原位裸鼠模型中的肝转移，但不抑制肿瘤发生。此外，通过表达IkappaBalphaM抑制NF κ B活化显著降低了主要促血管生成分子血管内皮生长因子的体内表达，因此降低了肿瘤性血管生成。通过表达IkappaBalphaM和使用药理学NF κ B抑制剂PS-341来抑制NF κ B活化也显著降低了AsPc-1胰腺癌细胞中马槟榔诱导的血管内皮生长因子和白细胞介素-8的表达。结论抑制NF κ B信号通路可抑制胰腺癌的血管生成和转移，提示NF κ B信号通路可能是抗肿瘤药物的潜在靶点。
PURPOSE We seek to elucidate the role of constitutive nuclear factor kappaB (NFkappaB) activity in human pancreatic cancer cells. We have demonstrated that the transcription factor NFkappaB is activated constitutively 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 NFkappaB plays a critical role in development of pancreatic adenocarcinoma. EXPERIMENTAL DESIGN By pooling all of the puromycin resistant clones after inhibitor of nuclear factor-kappaB phosphorylation mutant (IkappaBalphaM) retroviral infection, we generated pancreatic tumor cell lines that express a IkappaBalphaM (S32, 36A) that blocks NFkappaB activity. Inhibition of metastatic phenotype was assayed in an orthotopic nude mouse model. NFkappaB activity was determined by electrophoretic mobility shift assay, and the expression of NFkappaB downstream target genes was analyzed by Northern, Western, and immunohistochemical analyses. RESULTS We showed that inhibiting constitutive NFkappaB activity by expressing IkappaBalphaM suppresses liver metastasis, but not tumorigenesis, from the metastatic human pancreatic tumor cell line AsPc-1 in an orthotopic nude mouse model. Furthermore, inhibiting NFkappaB activation by expressing IkappaBalphaM significantly reduced in vivo expression of a major proangiogenic molecule, vascular endothelial growth factor, and, hence, decreased neoplastic angiogenesis. Inhibiting NFkappaB activation by expressing IkappaBalphaM and using pharmacologic NFkappaB inhibitor PS-341 also significantly reduced cytokine-induced vascular endothelial growth factor and interleukin-8 expression in AsPc-1 pancreatic cancer cells. CONCLUSION These results demonstrated that the inhibition of NFkappaB signaling can suppress the angiogenic potential and metastasis of pancreatic cancer, and suggest that the NFkappaB signaling pathway is a potential target for anticancer agents.