Abstract
The radioresistance of esophageal squamous cell carcinoma (ESCC) remains an obstacle for the effective radiotherapy of ESCC. This study aimed to investigate the radiosensitization of ESCC by signal transducer and activator of transcription 3 (STAT3) inhibitor stattic. ECA109, TE13, and KYSE150 cell lines were 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. In addition, ECA109 cells were xenografted into nude mice and treated with radiation and/or stattic. The levels of STAT3, p-STAT3, hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF) in ESCC cells and xenografts were detected by Western blot and immunohistochemical analysis. Our results showed that stattic efficiently radiosensitized ESCC cells and xenografts, especially under hypoxia. Moreover, stattic inhibited STAT3 activation and downregulated HIF-1α and VEGF expression. In conclusion, stattic confers radiosensitivity in ESCC cells in vitro and in vivo and is a potential adjuvant for the radiotherapy of ESCC in the clinical setting.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381(9864):400–12.
Karar J, Maity A. Modulating the tumor microenvironment to increase radiation responsiveness. Cancer Biol Ther. 2009;8(21):1994–2001.
Cummins EP, Taylor CT. Hypoxia-responsive transcription factors. Pflugers Arch. 2005;450(6):363–71.
Jung JE, Lee HG, Cho IH, et al. STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. FASEB J. 2005;19(10):1296–8.
Xu Q, Briggs J, Park S, et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene. 2005;24(36):5552–60.
Keith B, Johnson RS, Simon MC. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2011;12:9–22.
Huang CY, Lin CS, Tai WT, et al. Sorafenib enhances radiation-induced apoptosis in hepatocellular carcinoma by inhibiting STAT3. Int J Radiat Oncol Biol Phys. 2013;86(3):456–62.
Bu X, Zhao C, Wang W, et al. GRIM-19 inhibits the STAT3 signaling pathway and sensitizes gastric cancer cells to radiation. Gene. 2013;512(2):198–205.
Schust J, Sperl B, Hollis A, Mayer TU, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 2006;13(11):1235–42.
Leong PL, Andrews GA, Johnson DE, et al. Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci U S A. 2003;100(7):4138–43.
Zhong Z, Wen Z. Darnell JE Jr Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264:95–8.
Deng J, Liang H, Zhang R, Sun D, Pan Y, Liu Y, et al. STAT3 is associated with lymph node metastasis in gastric cancer. Tumour Biol. 2013;34:2791–800.
Wang T, Niu G, Kortylewski M, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nature Med. 2004;10:48–54.
Huang LE, Bindra RS, Glazer PM, Harris AL. Hypoxia-induced genetic instability: a calculated mechanism underlying tumor progression. J Mol Med (Berl). 2007;85:139–48.
Sohda M, Ishikawa H, Masuda N, Kato H, Miyazaki T, Nakajima M, et al. Pretreatment evaluation of combined HIF-1alpha, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer. Int J Cancer. 2004;110:838–84.
Moon SY, Chang HW, Roh JL, Kim GC, Choi SH, Lee SW, et al. Using YC-1 to overcome the radioresistance of hypoxic cancer cells. Oral Oncol. 2009;45:915–9.
Staab A, Fleischer M, Loeffler J, Said HM, Katzer A, Plathow C, et al. Small interfering RNA targeting HIF-1alpha reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro. Strahlenther Onkol. 2011;187:252–9.
Gray MJ, Zhang J, Ellis LM, et al. HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene. 2005;24:3110–20.
Han Z, Feng J, et al. Silencing of the STAT3 signaling pathway reverses the inherent and induced chemoresistance of human ovarian cancer cells. Biochem Biophys Res Commun. 2013;435(2):188–94.
Schust J, Sperl B, Hollis A, Mayer TU, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 2006;13:1235–42.
Pan Y, Zhou F, Zhang R, Claret FX. Stat3 inhibitor stattic exhibits potent antitumor activity and induces chemo- and radio-sensitivity in nasopharyngeal carcinoma. PLoS ONE. 2013;8(1):e54565.
Adachi M, Cui C, Dodge CT, Bhayani MK, Lai SY. Targeting STAT3 inhibits growth and enhances radiosensitivity in head and neck squamous cell carcinoma. Oral Oncol. 2012;48:1220–6.
Bonner JA, Trummell HQ, Willey CD, Plants BA, Raisch KP. Inhibition of STAT-3 results in radiosensitization of human squamous cell carcinoma. Radiother Oncol. 2009;92(3):339–44.
Yang X, Yang B, Cai J. Berberine enhances radiosensitivity of esophageal squamous cancer by targeting HIF-1α in vitro and in vivo. Cancer Biol Ther. 2013;14:1068–73.
Conflicts of interest
None
Author information
Authors and Affiliations
Corresponding author
Additional information
Qu Zhang, Chi Zhang, and Jia He contributed equally
Rights and permissions
About this article
Cite this article
Zhang, Q., Zhang, C., He, J. et al. STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma. Tumor Biol. 36, 2135–2142 (2015). https://doi.org/10.1007/s13277-014-2823-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-014-2823-y