Identification of ING4 (Inhibitor of Growth 4) as a Modulator of Docetaxel Sensitivity in Human Lung Adenocarcinoma
Identification of ING4 (Inhibitor of Growth 4) as a Modulator of Docetaxel Sensitivity in Human Lung Adenocarcinoma
复制标题
鉴定 ING4（生长抑制剂 4）作为人肺腺癌多西紫杉醇敏感性调节剂
DOI：
10.2119/molmed.2011.00230
复制
发表时间：
2012-05-01
影响因子：
5.7
通讯作者：
Chen, Longbang
中科院分区：
文献类型：
--
作者：
Wang, Rui;Huang, Jiayuan;Chen, Longbang
对多西紫杉醇（DTX）的耐药性通常发生在肺腺癌患者中。为了更好地阐明对 DTX 化疗耐药的潜在分子机制，我们建立了 DTX 耐药肺腺癌细胞系 (SPC-A1/DTX)。通过基因芯片分析，发现SPC-A1/DTX细胞中ING4的表达显着下调。此外，DTX 处理 SPC-A1 细胞后，诱导 ING4 基因表达降低。 ING4的过表达通过诱导细胞凋亡增强和G2/M阻滞来逆转DTX耐药肺腺癌细胞（SPC-A1/DTX或A549/Taxol）的DTX或紫杉醇耐药性，并且小干扰RNA介导的ING4敲低使DTX敏感肺腺癌细胞对DTX或紫杉醇更具耐药性。 紫杉醇。此外，ING4的过表达可以增强SPC-A1/DTX细胞对DTX的体内敏感性。 ING4过表达引起的SPC-A1/DTX细胞表型变化可能与Bcl-2/Bax比例降低，导致caspase-3激活有关。无反应患者肿瘤中ING4表达水平显着低于有反应者，提示ING4表达与肿瘤对DTX的反应呈正相关。我们的结果提供了第一个证据，表明 ING4 可能对肺腺癌的 DTX 耐药至关重要。因此，ING4将成为克服肺腺癌对DTX化疗耐药的潜在分子靶点。
Resistance to docetaxel (DTX) usually occurs in patients with lung adenocarcinoma. To better elucidate the underlying molecular mechanisms involved in resistance to DTX-based chemotherapy, we established a DTX-resistant lung adenocarcinoma cell line (SPC-A1/DTX). By gene array analysis, the expression of ING4 was found to be significantly downregulated in SPC-A1/DTX cells. Additionally, the decreased expression of the ING4 gene was induced upon DTX treatment of SPC-A1 cells. Overexpression of ING4 reverses DTX or paclitaxel resistance of DTX-resistant lung adenocarcinoma cells (SPC-A1/DTX or A549/Taxol) by inducing apoptosis enhancement and G2/M arrest, and small interfering RNA-mediated ING4 knockdown renders DTX-sensitive lung adenocarcinoma cells more resistant to DTX or paclitaxel. Also, overexpression of ING4 could enhance the in vivo sensitivity of SPC-A1/DTX cells to DTX. The phenotypical changes of SPC-A1/DTX cells induced by overexpression of ING4 might be associated with the decreased ratio of Bcl-2/Bax, which resulted in the activation of caspase-3. The level of ING4 expression in tumors of nonresponding patients was significantly lower than that in those of responders, suggesting that the expression of ING4 was positively correlated with tumor response to DTX. Our results provide the first evidence that ING4 might be essential for DTX resistance in lung adenocarcinoma. Thus, ING4 will be a potential molecular target for overcoming resistance to DTX-based chemotherapies in lung adenocarcinoma.