HDAC Inhibitor Vorinostat Enhances the Antitumor Effect of Gefitinib in Squamous Cell Carcinoma of Head and Neck by Modulating ErbB Receptor Expression and Reverting EMT
HDAC Inhibitor Vorinostat Enhances the Antitumor Effect of Gefitinib in Squamous Cell Carcinoma of Head and Neck by Modulating ErbB Receptor Expression and Reverting EMT
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DOI：
10.1002/jcp.22574
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发表时间：
2011-09-01
影响因子：
5.6
通讯作者：
Budillon, Alfredo
中科院分区：
文献类型：
--
作者：
Bruzzese, Francesca;Leone, Alessandra;Budillon, Alfredo
头颈部鳞状细胞癌（SCCHN）需要增强表皮生长因子受体（EGFR）抑制剂的作用以提高其治疗指数。我们证明了组蛋白脱乙酰酶抑制剂伏立诺他与EGFR酪氨酸激酶抑制剂吉非替尼联合诱导SCCHN细胞（包括吉非替尼耐药细胞）的增殖、迁移和侵袭的协同抑制以及凋亡的诱导。我们提供的证据表明，ErbB受体的差异调节以及伏立诺他逆转上皮-间质转化（EMT）代表了所观察到的协同作用的机制基础。我们证明在表达EGFR、ErbB 2和ErbB 3的上皮CAL 27细胞中，伏立诺他下调所有三种受体的表达和信号传导。在吉非替尼耐药KB和Hep-2细胞中，这两种细胞都经历了EMT并表达非常低水平的ErbB 3，伏立诺他通过诱导E-钙粘蛋白和ErbB 3并下调波形蛋白以及EGFR和ErbB 2来逆转间充质表型。伏立诺他对ErbB受体的调节涉及转录和翻译后机制。伏立诺他处理后，CAL 27细胞中所有ErbB转录物的减弱以及Hep-2和KB细胞中ErbB 3转录物的诱导。我们发现伏立诺他诱导EGFR和ErbB 2的泛素化，并在所有细胞系中主要将其靶向溶酶体降解，而在CAL 27细胞中诱导ErbB 3泛素化导致蛋白酶体降解。总体而言，这项研究表明，伏立诺他/吉非替尼组合代表了一种有前途的治疗策略，值得在SCCHN中进行进一步的临床评价，包括对EGFR抑制剂具有内在耐药性的肿瘤。J.细胞。226：2378-2390，2011。(C)2010 Wiley-Liss，Inc.
Potentiation of epidermal growth factor receptor (EGFR) inhibitors is required in squamous cell carcinoma of head and neck (SCCHN) to improve their therapeutic index. We demonstrated that the histone deacetylase inhibitor vorinostat in combination with the EGFR tyrosine kinase inhibitor gefitinib induced synergistic inhibition of proliferation, migration, and invasion as well as induction of apoptosis in SCCHN cells, including cells resistant to gefitinib. We provided evidence suggesting that differential modulation of ErbB receptors together with reversion of epithelial-to-mesenchymal transition (EMT) by vorinostat represent mechanistic bases for the observed synergism. We demonstrated in epithelial CAL27 cells expressing EGFR, ErbB2, and ErbB3 that vorinostat downregulated the expression and signaling of all three receptors. In gefitinib-resistant KB and Hep-2 cells, both of which had undergone EMT and expressed very low levels of ErbB3, vorinostat reverted the mesenchymal phenotype by inducing both E-cadherin and ErbB3 and downregulating vimentin as well as EGFR and ErbB2. Both transcriptional and post-translational mechanisms were involved in the modulation of ErbB receptors by vorinostat. Attenuation of all ErbB transcripts in CAL27 cells as well as induction of ErbB3 transcript in Hep-2 and KB cells was seen upon vorinostat treatment. We showed that vorinostat induced ubiquitination of EGFR and ErbB2 and targeted them predominantly to lysosome-degradation in all cell lines, while the induction of ErbB3-ubiquitination in CAL27 cells led to proteasomes-degradation. Overall, this study suggests that the vorinostat/gefitinib combination represents a promising therapeutic strategy that warrants further clinical evaluation in SCCHN, including tumors intrinsically resistant to EGFR-inhibitors. J. Cell. Physiol. 226: 2378-2390, 2011. (C) 2010 Wiley-Liss, Inc.