Ixazomib Induces Apoptosis and Suppresses Proliferation in Esophageal Squamous Cell Carcinoma through Activation of the c-Myc/NOXA Pathway

Esophageal squamous cell carcinoma (ESCC) is one of the major subtypes of esophageal Cancer. More than half of the patients with ESCC in the world are in China, and the 5-year survival rate is less than 10%. As a new oral Proteasome Inhibitor, ixazomib has shown strong therapeutic effect in many solid tumors. In this study, we aimed to investigate the effects of ixazomib on the proliferation inhibition and Apoptosis of ESCC cells. We used four human ESCC cell lines, cell viability assay, cell cycle and Apoptosis assay, reverse-transcription polymerase chain reaction (RT-PCR), Western blot, immunohistochemistry, and ESCC xenografts model to clarify the roles of the therapeutic effect and mechanism of ixazomib in ESCC. Ixazomib significantly inhibited the proliferation and induced Apoptosis in ESCC cells. RT-PCR results showed that the expressions of endoplasmic reticulum stress-related gene phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) and MYC proto-oncogene (c-Myc) significantly increase after treatment with ixazomib in ESCC cells. When we knocked down the NOXA and c-Myc by small interfering RNA, the therapeutic effect of ixazomib markedly decreased, which confirmed that c-Myc/NOXA pathway played a key role in the treatment of ESCC with ixazomib. In vivo, the xenograft ESCC model mice were given 10 mg/kg of ixazomib every other day for 30 days. The results showed that the tumor size in the treatment group was significantly smaller than the control group. These results suggested that ixazomib is known to suppress proliferation and induce Apoptosis in ESCC cell lines, and this effect was likely mediated by increased activation of the c-Myc/NOXA signaling pathways. SIGNIFICANCE STATEMENT: Esophageal squamous cell carcinoma (ESCC) is the common worldwide malignant tumor, but conventional chemotherapeutics suffer from a number of limitations. In this study, the results suggested that ixazomib suppresses proliferation and induces Apoptosis in ESCC cell lines. Therefore, ixazomib may be a potential new strategy for ESCC therapy.