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Abstract

Purpose: Previous studies revealed diverging results regarding the role of survivin in squamous cell carcinoma of the head and neck(SCCHN). This study aimed to evaluate the clinical significance of survivin expression in SCCHN; the function of survivin in DNA-damage repair following ionizing radiation therapy (RT) in SCCHN cells; and the potential of honokiol to enhance RT through downregulation of survivin.

Experimental Design: Expression of survivin in SCCHN patient primary tumor tissues (n = 100) was analyzed and correlated with clinical parameters. SCCHN cell lines were used to evaluate the function of survivin and the effects of honokiol on survivin expression in vitro and in vivo

Results: Overexpression of survivin was significantly associated with lymph nodes' metastatic status (P = 0.025), worse overall survival (OS), and disease-free survival (DFS) in patients receiving RT (n = 65, OS: P = 0.024, DFS: P = 0.006) and in all patients with SCCHN (n = 100, OS: P = 0.002, DFS: P = 0.003). In SCCHN cells, depletion of survivinled to increased DNA damage and cell death following RT, whereas overexpression of survivin increased clonogenic survival. RT induced nuclear accumulation of survivin and its molecular interaction with γ-H2AX and DNA-PKCs. Survivin specifically bound to DNA DSB sites induced by I-SceI endonuclease. Honokiol (which downregulates survivin expression) in combination with RT significantly augmented cytotoxicity in SCCHN cells with acquired radioresistance and inhibited growth in SCCHN xenograft tumors.

Conclusions:Survivin is a negative prognostic factor and is involved in DNA-damage repair induced by RT. Targeting survivin using honokiol in combination with RT may provide novel therapeutic opportunities. 

Author information

Wang X1, Beitler JJ2, Huang W2, Chen G2, Qian G1, Magliocca K3, Patel MR4, Chen AY4, Zhang J5, Nannapaneni S1, Kim S6, Chen Z6, Deng X2, Saba NF1, Chen ZG1, Arbiser JL7,8, Shin DM9.

1 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
2 Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
3 Department of Pathology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
4 Department of Otolaryngology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
5 Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, Iowa.
6 Department of Biostatistics and Bioinformatics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
7 Department of Dermatology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
8 Veterans Affairs Medical Center, Decatur, Georgia.
9 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia. dmshin@emory.edu.