EGFR inhibition induces proinflammatory cytokines via NOX4 in HNSCC.
EGFR inhibition induces proinflammatory cytokines via NOX4 in HNSCC.
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DOI：
10.1158/1541-7786.mcr-13-0187
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Simons AL
中科院分区：
文献类型：
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作者：
Fletcher EV;Love-Homan L;Sobhakumari A;Feddersen CR;Koch AT;Goel A;Simons AL
慢性炎症在肿瘤的促进、迁移和侵袭中起着重要作用。通过微阵列分析，我们观察到表皮生长因子受体抑制剂（EGFRI）处理的头颈部鳞状细胞癌（HNSCC）细胞系中参与促炎途径的基因与各自的载体处理细胞系相比有显著增加。我们假设EGFRIs的功效可能被这些药物在HNSCC肿瘤细胞中产生的促炎反应所抵消。我们发现临床egfri如厄洛替尼、西妥昔单抗、拉帕替尼和帕尼单抗可诱导IL-2、IL-4、IL-6、IL-8、GM-CSF、TNFα和IFNγ等促炎细胞因子的分泌。关注IL-6，我们发现厄洛替尼诱导IL-6 mRNA和蛋白表达的时间依赖性增加，外源性IL-6能够保护HNSCC细胞免受厄洛替尼诱导的细胞毒性。相反，IL-6受体拮抗剂tocilizumab在体外和体内均使HNSCC细胞对厄洛替尼敏感。nf - κ b、p38和JNK抑制剂抑制厄洛替尼诱导的IL-6表达，提示nf - κ b和MAPK通路在IL-6表达中起重要作用。此外，下调NADPH氧化酶4 （NOX4）可抑制厄洛替尼诱导的促炎细胞因子的表达。综上所述，这些结果表明临床EGFRIs通过NOX4诱导促炎细胞因子的表达。因此，在HNSCC中，EGFRIs的抗肿瘤活性可能通过激活nox4介导的促炎通路而部分降低。
Chronic inflammation plays a significant role in tumor promotion, migration and invasion. Using microarray analysis, we observed a profound increase in genes involved in pro-inflammatory pathways in epidermal growth factor receptor inhibitor (EGFRI)-treated head and neck squamous cell carcinoma (HNSCC) cell lines compared to their respective vehicle-treated cell lines. We hypothesized that the efficacy of EGFRIs may be offset by the pro-inflammatory response that these drugs produce in HNSCC tumor cells. We found that clinical EGFRIs such as erlotinib, cetuximab, lapatinib and panitumumab induced the secretion of pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-8, GM-CSF, TNFα and IFNγ. Focusing on IL-6, we found that erlotinib induced a time-dependent increase in IL-6 mRNA and protein expression and exogenous IL-6 was able to protect HNSCC cells from erlotinib-induced cytotoxicity. Conversely, an IL-6 receptor antagonist tocilizumab, sensitized HNSCC cells to erlotinib in vitro and in vivo. Inhibitors of NFκB, p38 and JNK suppressed erlotinib-induced IL-6 expression, suggesting an important role of NFκB and MAPK pathways in IL-6 expression. Furthermore, knockdown of NADPH oxidase 4 (NOX4) suppressed erlotinib-induced pro-inflammatory cytokines expression. Taken together, these results suggest that clinical EGFRIs induce the expression of pro-inflammatory cytokines via NOX4. Therefore, the anti-tumor activity of EGFRIs may be partially reduced by activation of NOX4-mediated pro-inflammatory pathways in HNSCC.