HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma
HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma
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DOI：
10.2147/ott.s245813
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Chen, Size
中科院分区：
文献类型：
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作者：
Guan, Liuliu;Zou, Qingqing;Chen, Size
目的：目前，缺乏治疗食管鳞状细胞癌（ESCC）的经典有效药物是一个主要问题。c-Myc （MYC）蛋白是一个有希望的靶标，因为它在ESCC中过表达。MYC是热休克蛋白90 （HSP90）的敏感客户蛋白，因此，通过抑制HSP90靶向HSP90-MYC轴是ESCC的潜在治疗策略。在这里，我们评估了HSP90抑制剂（Ganetespib, STA-9090）作为myc阳性ESCC的抗癌药物的临床应用价值。材料和方法：我们首先分析ESCC组织微阵列和临床组织样本以确定MYC表达。采用免疫共沉淀法和免疫荧光法分析MYC与HSP90的关系。在体外细胞模型中，使用CCK-8试剂盒分析细胞生长，使用Western blot分析MYC蛋白表达。在两种异种移植动物模型中评估STA-9090的体内抗肿瘤活性。结果：我们通过抑制ESCC细胞增殖、细胞周期进展和存活，证明myc过表达的ESCC细胞对STA-9090处理高度敏感。此外，STA-9090处理降低了MYC表达，缩短了MYC蛋白的半衰期。我们进一步利用ESCC细胞和临床ESCC样本建立了两种异种移植小鼠模型，以验证STA-9090在体内的有效性。在这两种异种移植模型中，STA-9090在体内显著抑制myc阳性ESCC肿瘤的生长。相比之下，STA-9090治疗对低myc表达的ESCC肿瘤小鼠没有任何有益作用。结论：综上所述，我们的数据支持HSP90抑制剂STA-9090抑制MYC蛋白的表达并干扰HSP90-MYC蛋白-蛋白相互作用。从而在体外抑制ESCC细胞增殖，促进ESCC细胞凋亡，在体内减少ESCC肿瘤。基于我们的研究结果，我们建议STA-9090是myc阳性ESCC的潜在新治疗靶点。
Purpose: Currently, the paucity of classical effective pharmacological drugs to treat esophageal squamous cell carcinoma (ESCC) is a major problem. The c-Myc (MYC) protein is a promising target as it is overexpressed in ESCC. MYC is a sensitive client protein of the heat shock protein 90 (HSP90) and, therefore, targeting the HSP90-MYC axis by inhibition of HSP90 is a potential therapeutic strategy for ESCC. Here, we evaluated the clinical application value of the HSP90 inhibitor (Ganetespib, STA-9090) as an anti-cancer agent for MYC-positive ESCC.Materials and Methods: We first analyzed ESCC tissue microarrays and clinical tissue samples to determine MYC expression. The relationship between MYC and HSP90 was analyzed by co-immunoprecipitation assays and immunofluorescence. In in vitro cell models, cell growth was analyzed using the CCK-8 kit, and MYC protein expression was analyzed by Western blot. The in vivo antitumor activity of STA-9090 was assessed in two xenograft animal models.Results: We demonstrated that MYC-overexpressing ESCC cells were highly sensitive to STA-9090 treatment through suppressing ESCC cell proliferation, cell cycle progression and survival. Moreover, STA-9090 treatment decreased MYC expression, reducing the half-life of the MYC protein. We further established two xenograft mouse models using ESCC cells and clinical ESCC samples to validate the effectiveness of STA-9090 in vivo. In both xenograft models, STA-9090 substantially inhibited the growth of MYC-positive ESCC tumors in vivo. In contrast, STA-9090 treatment demonstrated no beneficial effects in mice with low-MYC expressing ESCC tumors.Conclusion: In conclusion, our data support that the HSP90 inhibitor, STA-9090, suppresses the expression of the MYC protein and interferes with HSP90-MYC protein-protein interaction. This, in turn, leads to inhibition of ESCC cell proliferation and promotion of apoptosis in ESCC cells in vitro and reduction of ESCC tumors in vivo. We propose, based on our findings, that STA-9090 is a potential novel therapeutic target for MYC-positive ESCC.