STAT3 inhibitors for cancer therapy: Have all roads been explored?
STAT3 inhibitors for cancer therapy: Have all roads been explored?
复制标题
DOI：
10.4161/jkst.22882
复制
发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Baran-Marszak F
中科院分区：
文献类型：
--
作者：
Fagard R;Metelev V;Souissi I;Baran-Marszak F
信号转导子和转录激活子STAT 3是在正常细胞生长中起关键作用的转录因子，并且在约70%的实体癌和血液癌中被组成性激活。活化的STAT 3在酪氨酸上磷酸化，并通过磷酸酪氨酸/src同源2（SH 2）结构域相互作用形成二聚体。二聚体通过与输入蛋白相互作用进入细胞核并结合靶基因。STAT 3的抑制导致肿瘤细胞死亡，这表明它是抗癌策略的有价值的靶标;最近发现基因内的激活突变证实了这一观点。然而，仍然只有少量的STAT 3直接抑制剂;此外，STAT 3与STAT 1（另一个主要针对凋亡，细胞死亡和防御病原体的STAT家族成员）的高度相似性要求STAT 3抑制剂对STAT 1没有影响。特异性的STAT 3直接抑制剂由SH 2配体组成，包括G四联体寡脱氧核苷酸（ODN）和小分子，它们诱导其中STAT 3被激活的肿瘤细胞的细胞死亡。STAT 3也可以被诱饵ODN（dODN）抑制，其结合STAT 3并诱导细胞死亡。已经设计了不干扰STAT 1介导的干扰素诱导的细胞死亡的特异性STAT 3 dODN，其指向STAT 3 DBD作为特异性抑制的靶标。该区域的综合分析正在实验室中进行，以设计具有STAT 3/STAT 1区分能力的DBD靶向STAT 3抑制剂。
The signal transducer and activator of transcription STAT3 is a transcription factor which plays a key role in normal cell growth and is constitutively activated in about 70% of solid and hematological cancers. Activated STAT3 is phosphorylated on tyrosine and forms a dimer through phosphotyrosine/src homology 2 (SH2) domain interaction. The dimer enters the nucleus via interaction with importins and binds target genes. Inhibition of STAT3 results in the death of tumor cells, this indicates that it is a valuable target for anticancer strategies; a view that is corroborated by recent findings of activating mutations within the gene. Yet, there is still only a small number of STAT3 direct inhibitors; in addition, the high similarity of STAT3 with STAT1, another STAT family member mostly oriented toward apoptosis, cell death and defense against pathogens, requires that STAT3-inhibitors have no effect on STAT1. Specific STAT3 direct inhibitors consist of SH2 ligands, including G quartet oligodeoxynucleotides (ODN) and small molecules, they induce cell death in tumor cells in which STAT3 is activated. STAT3 can also be inhibited by decoy ODNs (dODN), which bind STAT3 and induce cell death. A specific STAT3 dODN which does not interfere with STAT1-mediated interferon-induced cell death has been designed pointing to the STAT3 DBD as a target for specific inhibition. Comprehensive analysis of this region is in progress in the laboratory to design DBD-targeting STAT3 inhibitors with STAT3/STAT1 discriminating ability.