Bancroft Caren C, Chen Zhong, Yeh Jason, Sunwoo John B, Yeh Ning T, Jackson Sadhana, Jackson Chad, Van Waes Carter
Tumor Biology Section, Head and Neck Surgery Branch, The National Institute on Deafness and Other Communication Disorders, The National Institutes of Health, Bethesda, MD 20892, USA.
Int J Cancer. 2002 Jun 1;99(4):538-48. doi: 10.1002/ijc.10398.
We previously reported that expression of angiogenesis factors interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) is promoted by coactivation of transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) by interleukin-1alpha in human head and neck squamous cell carcinomas (HNSCC). However, expression of IL-1 receptor antagonist incompletely blocked reporter gene activity and cytokine expression, suggesting that other upstream signals may contribute to activation. Overexpression and autocrine activation of epidermal growth factor receptor (EGFR) is detected in 90% of HNSCC, and EGFR inhibitors have been reported to inhibit IL-8 and VEGF expression, but the intermediary signal pathways and transcription factors by which EGFR modulates proangiogenic factors is unknown. EGFR can activate the phosphotidylinositol-3 kinase (PI3K) and mitogen-activated/extracellular signal-regulated kinase (MEK) pathways, which can potentially modulate activation of NF-kappaB and AP-1, respectively. In our study, we examined the effect of EGF and antagonists of EGFR, PI3K and MEK on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in HNSCC cell lines UM-SCC-9 and 11B in which EGFR is overexpressed and activated. Recombinant EGF induced EGFR phosphorylation, activation of NF-kappaB and AP-1 reporter genes and IL-8 and VEGF expression, indicating that EGFR can mediate coactivation of both transcription factors and cytokine genes in HNSCC. EGFR antagonist PD153035 and anti-EGFR antibody C225 completely inhibited EGF-induced reporter activity and cytokine expression, but only partially inhibited constitutive activity. MEK inhibitor U0126 preferentially blocked AP-1 activity and expression of both IL-8 and VEGF, while PI3K inhibitor LY-294002 or a dominant negative inhibitor-kappaB preferentially blocked NF-kappaB activation and expression of IL-8 but not VEGF. EGFR, PI3K and MEK antagonists inhibited growth of HNSCC. We conclude that antagonists of EGFR, PI3K and MEK signal pathways have inhibitory activity against EGFR-induced NF-kappaB and AP-1 activation, IL-8 and VEGF expression and growth by HNSCC. Published 2002 Wiley-Liss, Inc.
我们先前报道，在人头颈部鳞状细胞癌（HNSCC）中，白细胞介素-1α通过转录因子核因子-κB（NF-κB）和激活蛋白-1（AP-1）的共激活促进血管生成因子白细胞介素-8（IL-8）和血管内皮生长因子（VEGF）的表达。然而，白细胞介素-1受体拮抗剂的表达并未完全阻断报告基因活性和细胞因子表达，这表明其他上游信号可能参与激活过程。在90%的HNSCC中检测到表皮生长因子受体（EGFR）的过表达和自分泌激活，并且有报道称EGFR抑制剂可抑制IL-8和VEGF的表达，但EGFR调节促血管生成因子的中间信号通路和转录因子尚不清楚。EGFR可激活磷脂酰肌醇-3激酶（PI3K）和丝裂原活化/细胞外信号调节激酶（MEK）通路，这两条通路可能分别调节NF-κB和AP-1的激活。在我们的研究中，我们检测了表皮生长因子（EGF）以及EGFR、PI3K和MEK拮抗剂对HNSCC细胞系UM-SCC-9和11B中NF-κB和AP-1激活以及IL-8和VEGF表达的影响，在这两种细胞系中EGFR过表达且被激活。重组EGF诱导EGFR磷酸化、NF-κB和AP-1报告基因的激活以及IL-8和VEGF的表达，表明EGFR可介导HNSCC中两种转录因子和细胞因子基因的共激活。EGFR拮抗剂PD153035和抗EGFR抗体C225完全抑制了EGF诱导的报告基因活性和细胞因子表达，但仅部分抑制了组成性活性。MEK抑制剂U0126优先阻断AP-1活性以及IL-8和VEGF的表达，而PI3K抑制剂LY-294002或显性负性抑制剂-κB优先阻断NF-κB的激活以及IL--8的表达，但不影响VEGF的表达。EGFR、PI3K和MEK拮抗剂抑制了HNSCC的生长。我们得出结论，EGFR、PI3K和MEK信号通路的拮抗剂对EGFR诱导的NF-κB和AP-1激活、IL-8和VEGF表达以及HNSCC的生长具有抑制活性。2002年由Wiley-Liss公司出版。
