GC7 enhances cisplatin sensitivity via STAT3 signaling pathway inhibition and eIF5A2 inactivation in mesenchymal phenotype oral cancer cells

Fang,Liang; Gao,Li; Xie,Lei; Xiao,Guizhou

doi:10.3892/or.2017.6161

GC7 enhances cisplatin sensitivity via STAT3 signaling pathway inhibition and eIF5A2 inactivation in mesenchymal phenotype oral cancer cells

Authors:
- Liang Fang
- Li Gao
- Lei Xie
- Guizhou Xiao
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Affiliations: Department of Head and Neck Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
Published online on: December 15, 2017 https://doi.org/10.3892/or.2017.6161
Pages: 1283-1291

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Abstract

Eukaryotic initiation factor 5A2 (eIF5A2), a newly identified oncogene, promotes cell survival, proliferation and motility in tumorigenesis. Drug resistance and dose-related adverse side-effects greatly reduce the efficiency and safety of cisplatin-based chemotherapy in advanced or recurrent oral squamous cell carcinoma (OSCC) patients. The present study investigated the effect of eIF5A2 combined with N1-guanyl-1,7-diaminoheptane (GC7, a novel eIF5A2 inhibitor) or siRNA. We found that low concentrations of GC7 (≤5 µM) had little effect on OSCC cell viability, but significantly enhanced cisplatin cytotoxicity. Compared with cisplatin, GC7/cisplatin had little effect on cisplatin-promoted mesenchymal-epithelial transition in mesenchymal phenotype Tca8113 and HN30 cells, or on cisplatin-induced epithelial-mesenchymal transition (EMT) in epithelial phenotype Cal27 and HN4 cells. Further research revealed that the upregulation of p-STAT3 and c-Myc which was induced by the single treatment with either cisplatin or GC7 was significantly reversed by the GC7/cisplatin combination in mesenchymal phenotype Tca8113 and HN30 cells. In in vivo treatment, we revealed that the GC7/cisplatin combination presented significant tumor volume reduction without distinct body weight loss. In conclusion, our data indicated that eIF5A2 is a potent therapeutic target in OSCC treatment. Our results revealed a novel mechanism by which GC7/cisplatin combination therapy may offer an efficient and safe therapeutic alternative to advanced or recurrent OSCC patients.

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