Mechanism of radiosensitization effect of Stattic on human esophageal squamous cellcarcinoma in hypoxia

Abstract

Objective To investigate the radiosensitivity of ESCC by signal transducer and activator of transcription 3 (STAT3) inhibitor Stattic, since the radioresistance of esophageal squamous cell carcinoma(ESCC) remains an obstacle for the effective radiotherapy of ESCC. Methods ECA109 cell line was exposed to hypoxia and treated with Stattic or radiation, alone or in combination. Cell proliferation, colony formation, apoptosis, and double-stranded DNA breaks (DSBs) were examined. The levels of STAT3, pSTAT3, hypoxiainduciblefactor1α(HIF-1α), and vascular endothelial growthfactor (VEGF) in ESCC cells were detected by Western blot. Results Stattic efficiently inhibited the proliferation of ECA109 cells in time-dependent and dose-dependent fashions with an IC50 of 5.499 μmol/ L. Clonogenic survival assay showed that stattic (1.0 μmol/L) sensitized ECA109 cells to ionizing radiation and its SERDo was 1.20(in normoxia) or 1.28(in hypoxia). Under hypoxic condition, stattic combined with IR disrupted the repair of DSBs and increased the apoptosis(t=7.33, P<0.05) in ESCC cells compared to that of radiation treatment alone. Moreover, Western blot assay showed that stattic inhibited STAT3 activation and downregulated the expression level of pSTAT3 and HIF-1α and VEGF. Conclusions Stattic confers radiosensitivity in ESCC cells in vitro and is a potential adjuvant for the radiotherapy of ESCC in the clinical setting. Key words: Stattic; Esophageal squamous cell carcinoma; Radiosensitivity; Hypoxiainduciblefactor 1α; Vascular endothelial growthfactor