Honokiol Radiosensitizes Squamous Cell Carcinoma of the Head and Neck by Downregulation of Survivin

Abstract
Background: Overexpression of survivin is associated with resistance to radiotherapy and poor survival in many cancer types. However, in squamous cells carcinoma of head and neck (SCCHN), previous studies have revealed diverging results regarding survivin's role in clinical outcome. In this study, we aim to 1) evaluate the clinical significance of survivin expression in SCCHN; 2) identify the function of survivin on DNA damage repair following ionizing radiation (IR) in SCCHN cells; 3) investigate the potential of using honokiol, a nature compound, to enhance radiation therapy through down regulation of survivin. Methods: Protein expression of survivin in SCCHN patient primary tissues (n = 99) was analyzed by immunohistochemistry and correlated with clinical parameters. IR-sensitive (JHU-022), IR -insensitive (PCI-15A, Tu212), and IR acquired resistance (PCI-15A-R) SCCHN cell lines were used to evaluate the role of survivin in DNA double strain break repairer following RT. The in vitro effects of and potential molecular targets of honokiol were also evaluated using those cell lines. Results: Overexpression of survivin is significantly associated with lymph node metastasis, worse overall survival and worse disease free survival in patients receiving radiation therapy (n = 65) and in all patients with SCCHN (n = 99). In SCCHN cells, depletion of survivin by siRNA inhibited, whereas overexpression of survivin increased, clonogenic survival following IR. IR induces nuclear accumulation of survivin and complexation with γ-H2X, and DNA-PKCs, suggesting survivin is involved in DNA damage response and repair induced by IR. Further, honokiol significantly reduces survivin expression and increases DNA damage induced by IR, as demonstrated by higher amount of DNA breaks and an increased amount of γ-H2X foci post IR. Conclusions: Survivin is a negative prognostic factor in SCCHN, and is involved in DNA damage response and repair induced by IR in SCCHN cells. Down regulation of survivin by honokiol enhances the efficacy of IR, and may provide a novel therapeutic approach to improve the efficacy of radiotherapy in SCCHN.
出版源：《Clinical Cancer Research An Official Journal of the American Association for Cancer Research》2017