Abstract
Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. VEGF was reported to promote the occurrence of autophagy, which enhanced the radioresistance of tumors. The purpose of this study was to investigate the influence of VEGF silencing on the radiosensitivity of nasopharyngeal carcinoma (NPC) cells and the underlying mechanisms. The radiosensitivity of NPC cells after VEGF silencing was detected by cell counting kit 8 (CCK-8) and clonogenic assay, while cell cycle and apoptosis were detected by flow cytometry. The processes of DNA damage, repair and autophagy were examined by immunofluorescence and western blotting. The interaction between VEGF and mTOR was confirmed by western blotting and co-immunoprecipitation studies. The effect of VEGF on radiosensitivity of NPC cells was investigated in vivo using a xenograft model. Furthermore, immunohistochemistry and TUNEL assays were used to verify the relationship between autophagy and radiosensitivity in NPC after VEGF depletion. Downregulation of VEGF significantly inhibited cell proliferation and induced apoptosis of NPC cells after radiotherapy in vitro and in vivo. In addition, VEGF knockdown not only decreased autophagy level, but also delayed the DNA damage repair in NPC cells after irradiation. Mechanistically, silencing VEGF suppressed autophagy through activation of the mTOR pathway. VEGF depletion increased radiosensitivity of NPC cells by suppressing autophagy via activation of the mTOR pathway.
Highlights
Nasopharyngeal carcinoma (NPC) is a common tumor in Southeast Asia especially in southern China, with an annual incidence of about 20 cases per 100,000 p eople[1]
Our team has established the nasopharyngeal carcinoma (NPC) radioresistant cell line CNE-2R derived from the CNE-2 cells
Vascular endothelial growth factor (VEGF) regulates autophagy through the Mammalian target of rapamycin (mTOR) pathway. mTOR is known to be related to autophagy, so we further explored whether VEGF regulates autophagy through the mTOR pathway in NPC cells
Summary
Nasopharyngeal carcinoma (NPC) is a common tumor in Southeast Asia especially in southern China, with an annual incidence of about 20 cases per 100,000 p eople[1]. VEGF causes tumor cell reoxygenation, which leads to excessive DNA replication, increased synthesis of radioresistance genes, and r adioresistance[3]. Our previous study demonstrated that inhibition of autophagy enhances radiosensitivity of NPC cells[10], which was corroborated by Chu et al.[11]. VEGF inhibited autophagy, as evidenced by the finding that the autophagic flux and cell activity decreased significantly in VEGF-silenced tumor c ells[12]. Increasing evidence have demonstrated that mTOR inhibition activates the occurrence of autophagy[14]. Studies have indicated that VEGF is involved in the regulation of the mTOR pathway[15,16]. Whether VEGF regulates autophagy and affects radiosensitivity of NPC through the mTOR signaling pathway has not yet been clarified
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