NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells.
NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells.
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DOI：
10.1016/j.taap.2013.07.013
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发表时间：
2013-11-01
影响因子：
3.8
通讯作者：
Simons, Andrean L.
中科院分区：
文献类型：
--
作者：
Sobhakumari, Arya;Schickling, Brandon M.;Love-Homan, Laurie;Raeburn, Ayanna;Fletcher, Elise V. M.;Case, Adam J.;Domann, Frederick E.;Miller, Francis J., Jr.;Simons, Andrean L.
大多数头颈部鳞状细胞癌(HNSCC)过表达表皮生长因子受体(EGFR)和EGFR抑制剂是治疗HNSCC的常规药物。然而，许多HNSCC肿瘤对EGFR抑制剂没有反应或变得不耐药。自噬是一种应激诱导的细胞自我降解过程，已有报道在各种疾病模型中降低化疗的疗效。本研究的目的是确定EGFR抑制剂erlotinib是否通过NOX4介导的氧化应激激活HNSCC细胞中的自噬而降低其疗效。厄洛替尼诱导FaDu和Cal-27细胞表达自噬标志物LC3B-II并形成自噬小体。氯喹抑制自噬和敲除自噬途径基因Beclin-1和ATG5使两株细胞对厄洛替尼诱导的细胞毒敏感，提示自噬可能是一种保护机制。过氧化氢酶(CAT)和二苯基碘(DPI)与厄洛替尼联合作用可抑制FaDu和Cal-27细胞中LC3B-II表达的增加。厄洛替尼通过增强NOX4启动子活性和mRNA稳定性，增加了NOX4在FaDu细胞中的表达。用腺病毒siNOX4基因敲除NOX4可部分抑制厄洛替尼诱导的LC3B-II的表达，而过表达NOX4则增加了LC3B-II的表达。这些研究表明，厄洛替尼可能激活HNSCC细胞的自噬，作为一种促生存机制，NOX4可能在这一作用中起到中介作用。
Most head and neck squamous cell carcinomas (HNSCC) overexpress epidermal growth factor receptor (EGFR) and EGFR inhibitors are routinely used in the treatment of HNSCC. However, many HNSCC tumors do not respond or become refractory to EGFR inhibitors. Autophagy, which is a stress-induced cellular self-degradation process, has been reported to reduce the efficacy of chemotherapy in various disease models. The purpose of this study is to determine if the efficacy of the EGFR inhibitor erlotinib is reduced by activation of autophagy via NOX4-mediated oxidative stress in HNSCC cells. Erlotinib induced the expression of the autophagy marker LC3B-II and autophagosome formation in FaDu and Cal-27 cells. Inhibition of autophagy by chloroquine and knockdown of autophagy pathway genes Beclin-1 and Atg5 sensitized both cell lines to erlotinib-induced cytotoxicity, suggesting that autophagy may serve as a protective mechanism. Treatment with catalase (CAT) and diphenylene iodonium (DPI) in the presence of erlotinib suppressed the increase in LC3B-II expression in FaDu and Cal-27 cells. Erlotinib increased NOX4 mRNA and protein expression by increasing its promoter activity and mRNA stability in FaDu cells. Knockdown of NOX4 using adenoviral siNOX4 partially suppressed erlotinib-induced LC3B-II expression, while overexpression of NOX4 increased expression of LC3B-II. These studies suggest that erlotinib may activate autophagy in HNSCC cells as a pro-survival mechanism, and NOX4 may play a role in mediating this effect.
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DOI：
10.1073/pnas.1002178107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Kuroda, Junya;Ago, Tetsuro;Sadoshima, Junichi
通讯作者：
Sadoshima, Junichi
DOI：
10.1007/978-1-4020-6554-5_9
发表时间：
2008-01-01
期刊：
PROGRAMMED CELL DEATH IN CANCER PROGRESSION AND THERAPY
影响因子：
--
作者：
Bialik, Shani;Kimchi, Adi
通讯作者：
Kimchi, Adi
DOI：
10.1097/jto.0b013e318262de4a
发表时间：
2012-10
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Goldberg SB;Supko JG;Neal JW;Muzikansky A;Digumarthy S;Fidias P;Temel JS;Heist RS;Shaw AT;McCarthy PO;Lynch TJ;Sharma S;Settleman JE;Sequist LV
通讯作者：
Sequist LV
影响因子：
3.5
作者：
Harari, Paul M.;Wheeler, Deric L.;Grandis, Jennifer R.
通讯作者：
Grandis, Jennifer R.
影响因子：
11.2
作者：
Hu YL;Jahangiri A;Delay M;Aghi MK
通讯作者：
Aghi MK