(E) Images of tumors from all groups

(E) Images of tumors from all groups. 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 bene?cial 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 proteinCprotein interaction. This, in turn, leads to inhibition of ESCC cell proliferation and promotion Tasisulam sodium 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. strong class=”kwd-title” Keywords: esophageal squamous cell cancer, c-Myc, HSP90 inhibition, ?Ganetespib, STA-9090, patient-derived xenograft model Introduction Esophagus Cancer (EC) is a common malignant tumor ranked seventh and sixth in terms of prevalence and mortality rate respectively.1 The major classifications for EC pathology are esophagus adenocarcinoma (EAC) and esophagus squamous cell carcinoma (ESCC), with ESCC accounting for approximately 90% of all esophageal cancer cases worldwide. Recent epidemiological data show that approximately three quarters of new cases develop in countries with low to medium levels of socioeconomic development, and nearly half (49%) of all new cases occur in China.2 Many patients with ESCC are diagnosed at an advanced stage, and the mainstay treatments for ESCC such as surgery, chemotherapy, and radiotherapy have limited efficacy.3 The prognosis of EC is poor with a five-year survival rate of less than 20%.4 Although there are a few targeted drugs, such as monoclonal antibodies and tyrosine kinase inhibitors,3,5 that play important roles in treating advanced ESCC tumors, their effectiveness are still lacking.6 Therefore, there is a need for in-depth studies of the molecular mechanism of ESCC aiming at the discovery of new therapeutic targets for better patient outcome. C-Myc (MYC) is a member of a family of proto-oncogenes, which are transcription factors that regulate target gene transcription and induce malignant cell growth and proliferation.7C9 Members of the MYC family promote DNA synthesis and are important mediators in the transition from the G1 to S phase in the cell cycle. It is Tasisulam sodium estimated that MYC regulates 15% of gene expression in humans and promotes the expression of genes involved in tumor proliferation.10 The MYC protein has been reported to be commonly over-expressed in ESCC tumors with a positive expression rate of 61.05%.11 Recently, Rabbit Polyclonal to Mammaglobin B since starting this project, targeted MYC therapy using the bromodomain inhibitor, JQ1, has shown to be effective in suppressing ESCC tumors in pre-clinical models.12 Tasisulam sodium The heat shock protein 90 (HSP90) is a key regulator molecule that maintains protein homeostasis and cell survival.13 HSP90 is highly expressed in several cancers, including ESCC.14C16 Many client proteins of HSP90 are involved in cell cycle progression and cell survival. Inhibition of HSP90 leads to the degradation of client proteins and induces cell cycle arrest or apoptosis.17 MYC is a crucial client protein of HSP90 and the HSP90-MYC complex is important in cell cycle progression.18 The drug Ganetespib (STA-9090) is a second-generation HSP90 inhibitor that presents potent cytotoxicity in a range of solid and hematological tumors and demonstrates antitumor activity with promising safety profiles in vivo in a variety of cancers.19 At present, many Phase ICIII clinical trials of STA-9090 for human cancer treatment Tasisulam sodium are ongoing, including breast and lung cancers.20C24 As the HSP90-MYC has been shown to be critical in cancer cell proliferation and given MYC is highly expressed in.