HSP90 Inhibitor SNX5422/2112 Targets the Dysregulated Signal and Transcription Factor Network and Malignant Phenotype of Head and Neck Squamous Cell Carcinoma
HSP90 Inhibitor SNX5422/2112 Targets the Dysregulated Signal and Transcription Factor Network and Malignant Phenotype of Head and Neck Squamous Cell Carcinoma
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DOI：
10.1593/tlo.13292
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发表时间：
2013-08-01
影响因子：
5
通讯作者：
Van Waes, Carter
中科院分区：
文献类型：
--
作者：
Friedman, Jay A.;Wise, Stephanie C.;Van Waes, Carter
热休克蛋白90（HSP 90）是一种伴侣蛋白，其稳定参与上皮癌（包括头颈部鳞状细胞癌（HNSCC））的致癌和治疗抗性途径的蛋白。在这里，我们表征了HSP 90抑制剂SNX 5422/2112在HNSCC过表达HSP 90中的分子、细胞和临床前活性。SNX 2112在25 - 250 nM浓度范围内抑制细胞增殖，诱导G（2）/M阻滞，并增强细胞毒性、化疗敏感性和放射敏感性。SNX 2112在野生型（wt）TP 53缺陷型HNSCC系中显示与紫杉醇的组合活性，在突变型（mt）TP 53 HNSCC系中显示与顺铂的组合活性。SNX 2112降低表皮生长因子受体（EGFR）、c-MET、v-akt鼠胸腺瘤病毒癌基因同源物1（AKT）、细胞外信号调节激酶（ERK）1和2、抑制剂κ B激酶、信号转导和转录因子3（STAT 3）、相应下游核因子κ B、激活蛋白-1和STAT 3报告基因的表达或磷酸化，并靶向癌基因和血管生成细胞因子。此外，SNX 2112增强TP 53的再表达并靶向p21 WAF 1和p21 WAF A，而TP 53抑制剂Pifithrin或siRNA在体外减弱SNX 2112在wtTP 53 HNSCC中的抗增殖活性。前药SNX 5422类似地下调关键信号靶标，增强TP 53表达和凋亡，并抑制wtTP 53缺陷型HNSCC异种移植模型中的增殖、血管生成和肿瘤发生。因此，HSP 90抑制剂SNX 5422/2112广泛调节失调信号网络内的多个关键节点，对恶性表型具有相应的影响。我们的数据支持SNX 5422/2112联合紫杉醇、顺铂和放疗治疗不同TP 53状态的HNSCC的研究。
Heat shock protein 90 (HSP90) is a chaperone protein that stabilizes proteins involved in oncogenic and therapeutic resistance pathways of epithelial cancers, including head and neck squamous cell carcinomas (HNSCCs). Here, we characterized the molecular, cellular, and preclinical activity of HSP90 inhibitor SNX5422/2112 in HNSCC over-expressing HSP90. SNX2112 inhibited proliferation, induced G(2)/M block, and enhanced cytotoxicity, chemosensitivity, and radiosensitivity between 25 and 250 nM in vitro. SNX2112 showed combinatorial activity with paclitaxel in wild-type (wt) TP53-deficient and cisplatin in mutant (mt) TP53 HNSCC lines. SNX2112 decreased expression or phosphorylation of epidermal growth factor receptor (EGFR), c-MET, v-akt murine thymoma viral oncogene homolog 1 (AKT), extracellular signal-regulated kinases (ERK) 1 and 2, inhibitor kappa B kinase, and signal transducer and transcription factor 3 (STAT3), corresponding downstream nuclear factor kappa B, activator protein-1, and STAT3 reporter genes, and target oncogenes and angiogenic cytokines. Furthermore, SNX2112 enhanced re-expression of TP53 and targets p21WAF1 and PUMA, while TP53 inhibitor Pifithrin or siRNA attenuated the antiproliferative activity of SNX2112 in wtTP53 HNSCC in vitro. Prodrug SNX5422 similarly down-modulated key signal targets, enhanced TP53 expression and apoptosis, and inhibited proliferation, angiogenesis, and tumorigenesis in a wtTP53-deficient HNSCC xenograft model. Thus, HSP90 inhibitor SNX5422/2112 broadly modulates multiple key nodes within the dysregulated signaling network, with corresponding effects upon the malignant phenotype. Our data support investigation of SNX5422/2112 in combination with paclitaxel, cisplatin, and radiotherapy in HNSCC with different TP53 status.