Abstract 4758: Sensitization of nasopharyngeal carcinoma to radiotherapy by targeting GFPT1/TGF-β1 signaling pathways

Abstract

Abstract Background: Nasopharyngeal carcinoma (NPC) is a unique cancer with high susceptibility to radiation and mainstay treatment is radiotherapy. Effectiveness of NPC treatment is therefore dependent on the sensitivity of cancer cells to ionizing radiation treatment. Further, development of radio-resistant phenotype is a risk factor for distant metastasis and disease recurrence. Therefore, enhancing the degree of radiation sensitivity could improve prognosis and reduce the toxicity of radiotherapy with the use of lower radiation dose. Transforming growth factor β1(TGF-β1) expression is responsive to radiation treatment and the increase is important in the post-irradiation DNA repair. Tumor with low TGF-β1 level is more responsive to radiation treatment. Therefore, inhibiting TGF-β1 production can enhance the radiation damage to cancer cell DNA and also intensify the sensitivity of cancer cells to radiation. Our preliminary results indicate that TGF-β1 production in NPC is mediated by hexosamine pathway. Of which, GFPT1 (glucosamine-fructose-6-phosphate aminotransferase) is the rate-limiting enzyme. Purpose of the study: To enhance radiation sensitivity by targeting GFPT1/ TGF-β1 cascade in NPC. Experimental procedures: Radiation protective effects of TGF-β1 was examined by colony formation assay and Danio rerio (zebrafish) embryonic system. Production of TGF-β1 by activated hexosamine pathway in NPC was revealed by glucose and glucosamine treatment. Effects of GFPT1 silencing on radiosensitization are revealed by GFPT1 siRNA treatment followed by colony formation assay and gamma-H2AX formation assays. Results: Pretreatment of HONE1 cells with recombinant TGF-β1 protein enhanced the clonogenic ability of irradiated cells. TGF-β1 significantly increased the survival of zebrafish embryos after irradiation. Glucose and glucosamine treatment increased the expression of TGF-β1 protein in HONE1 cells. Silence of GFPT1 reduced TGF-β1 mRNA and protein expression in HONE1 cells. Silencing GFPT1 reduced the clonogenic capacity of head and neck cancer cells after radiotherapy and enhanced the degree of radiation-induced DNA double-strand breaks. Conclusions: Targeting GFPT1 enhances head and neck cancer cell sensitivity to radiation. GFPT1 inhibition can enhance the radiation sensitivity of head and neck cancer cells by inhibiting the expression of TGF-β1. Citation Format: Siqi Chen, Wei Gao, Jimmy Yu-Wai Chan, Thian-Sze Wong. Sensitization of nasopharyngeal carcinoma to radiotherapy by targeting GFPT1/TGF-β1 signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4758. doi:10.1158/1538-7445.AM2017-4758