Honokiol Radiosensitizes Squamous Cell Carcinoma of the Head and Neck by Downregulation of Survivin.
Honokiol Radiosensitizes Squamous Cell Carcinoma of the Head and Neck by Downregulation of Survivin.
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DOI：
10.1158/1078-0432.ccr-17-0345
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发表时间：
2018-02-15
期刊：
影响因子：
--
通讯作者：
Shin DM
中科院分区：
文献类型：
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作者：
Wang X;Beitler JJ;Huang W;Chen G;Qian G;Magliocca K;Patel MR;Chen AY;Zhang J;Nannapaneni S;Kim S;Chen Z;Deng X;Saba NF;Chen ZG;Arbiser JL;Shin DM
本研究旨在探讨Survivin在头颈部鳞状细胞癌(SCCHN)中表达的临床意义、Survivin在电离放射治疗(RT)后对SCCHN细胞DNA损伤修复中的作用以及和厚朴酚通过下调Survivin的表达来增强SCCHN细胞的RT。分析100例SCCHN患者原发肿瘤组织中Survivin的表达情况，并与临床参数进行相关性分析。采用SCCHN细胞株研究Survivin的功能及和厚朴酚对Survivin表达的影响。Survivin的高表达与放疗患者(n=65，OS：P=0.024，DFS：P=0.006)和所有SCCHN患者(n=100，OS：P=0.002，DFS：P=0.003)的淋巴结转移状态(P=0.025)、总生存期(OS：P=0.024，DFS：P=0.003)显著相关。在SCCHN细胞中，Survivin的缺失导致放疗后DNA损伤和细胞死亡增加，而Survivin的过表达则增加了克隆形成的存活率。RT诱导Survivin的核积聚及其与γ-H_2AX和DNA-PKCs的分子相互作用。I-SCEI内切酶诱导Survivin与DNA DSB位点特异性结合。和厚朴酚(下调Survivin表达)与RT联合应用可显著增强具有获得性放射抵抗的SCCHN细胞的细胞毒作用，并抑制SCCHN异种移植瘤的生长。Survivin是一种负向预后因子，参与了RT诱导的DNA损伤修复。靶向Survivin的和厚朴酚联合RT可能提供新的治疗机会。
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 radiationtherapy (RT) in SCCHN cells; and the potential of honokiol to enhance RT through downregulation of survivin. 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. 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 survivin led 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. 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.