Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B.
Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B.
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发表时间：
2003-10
影响因子：
5.7
通讯作者：
Lianne Fuino;P. Bali;S. Wittmann;S. Donapaty;F. Guo;H. Yamaguchi;Hong-Gang Wang;P. Atadja;K. B
中科院分区：
文献类型：
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作者：
Lianne Fuino;P. Bali;S. Wittmann;S. Donapaty;F. Guo;H. Yamaguchi;Hong-Gang Wang;P. Atadja;K. B
组蛋白去乙酰化酶抑制剂诱导核心核小体组蛋白的氨基末端赖氨酸残基的超乙酰化，这导致染色质重塑和改变的基因表达。目前的研究表明，暴露于一种新的异羟肟酸类似物组蛋白去乙酰化酶抑制剂，LAQ 824，诱导p21 WAF 1和p27 KIP 1，并导致具有扩增和过表达Her-2/neu的人乳腺癌SKBR-3和BT-474细胞的生长停滞和凋亡。用LAQ 824处理耗尽了Her-2/neu编码的Her-2的mRNA和蛋白水平，这与pAKT、c-Raf-1和磷酸化促分裂原活化蛋白激酶水平的衰减相关。LAQ 824还诱导热休克蛋白（hsp）90的乙酰化，导致其与ATP结合的抑制，这已显示损害hsp 90与其客户蛋白Her-2、AKT和c-Raf-1的伴侣缔合。与此一致，用LAQ 824处理将Her-2的结合从hsp 90转移到hsp 70，促进Her-2的蛋白酶体降解。因此，LAQ 824通过两种机制消耗Her-2：减弱其mRNA水平和促进其通过蛋白酶体的降解。LAQ 824处理后，细胞膜结合、自体酪氨酸磷酸化和HER-2与HER-3的共定位也下降。与LAQ 824共处理显著增加曲妥珠单抗诱导的BT-474和SKBR-3细胞凋亡。这与Her-2、c-Raf-1和pAKT水平的更大衰减相关。LAQ 824还增强了BT-474和SKBR-3细胞的紫杉醇诱导的、埃博霉素B诱导的和吉西他滨诱导的凋亡。这些发现表明LAQ 824对人乳腺癌细胞具有活性，并且具有改善曲妥珠单抗、泰索帝、吉西他滨和埃博霉素B对具有Her-2/neu扩增的乳腺癌的功效的潜力。
Histone deacetylase inhibitors induce hyperacetylation of the amino-terminal lysine residues of the core nucleosomal histones, which results in chromatin remodeling and altered gene expression. Present studies demonstrate that exposure to a novel hydroxamic acid analogue histone deacetylase inhibitor, LAQ824, induced p21WAF1 and p27KIP1 and caused growth arrest and apoptosis of human breast cancer SKBR-3 and BT-474 cells that possess amplification and overexpression of Her-2/neu. Treatment with LAQ824 depleted the mRNA and protein levels of Her-2/neu-encoded Her-2, which was associated with attenuation of pAKT, c-Raf-1, and phosphorylated mitogen-activated protein kinase levels. LAQ824 also induced the acetylation of heat shock protein (hsp) 90, resulting in inhibition of its binding to ATP, which has been shown to impair the chaperone association of hsp 90 with its client proteins, Her-2, AKT, and c-Raf-1. Consistent with this, treatment with LAQ824 shifted the binding of Her-2 from hsp 90 to hsp 70, promoting proteasomal degradation of Her-2. Thus, LAQ824 depletes Her-2 through two mechanisms: attenuation of its mRNA levels and promotion of its degradation by the proteasome. Following LAQ824 treatment, the cell membrane association, autotyrosine phosphorylation, and colocalization of Her-2 with HER-3 also declined. Cotreatment with LAQ824 significantly increased trastuzumab-induced apoptosis of BT-474 and SKBR-3 cells. This was associated with greater attenuation of Her-2, c-Raf-1, and pAKT levels. LAQ824 also enhanced taxotere-induced, epothilone B-induced, and gemcitabine-induced apoptosis of BT-474 and SKBR-3 cells. These findings suggest that LAQ824 is active against human breast cancer cells and has the potential to improve the efficacy of trastuzumab, taxotere, gemcitabine, and epothilone B against breast cancer with Her-2/neuamplification.