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首页> 外文期刊>Neurosurgical focus >Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin
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Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin

机译：药物引发可通过下调Survivin增强金刚烷性颅咽管瘤的放射敏感性

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OBJECTIVE In this study, the authors investigated the underlying mechanisms responsible for high tumor recurrence rates of adamantinomatous craniopharyngioma (ACP) after radiotherapy and developed new targeted treatment protocols to minimize recurrence. ACPs are characterized by the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR), known to mediate radioresistance in various tumor entities. The impact of tyrosine kinase inhibitors (TKIs) gefitinib or CUDC-101 on radiation-induced cell death and associated regulation of survivin gene expression was evaluated. METHODS The hypothesis that activated EGFR promotes radioresistance in ACP was investigated in vitro using human primary cell cultures of ACP (n = 10). The effects of radiation (12 Gy) and combined radiochemotherapy on radiosensitivity were assessed via cell death analysis using flow cytometry. Changes in target gene expression were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Survivin, identified in qRT-PCR to be involved in radioresistance of ACP, was manipulated by small interfering RNA (siRNA), followed by proliferation and vitality assays to further clarify its role in ACP biology. Immunohistochemically, survivin expression was assessed in patient tumors used for primary cell cultures. RESULTS In primary human ACP cultures, activation of EGFR resulted in significantly reduced cell death levels after radiotherapy. Treatment with TKIs alone and in combination with radiotherapy increased cell death response remarkably, assessed by flow cytometry. CUDC-101 was significantly more effective than gefitinib. The authors identified regulation of survivin expression after therapeutic intervention as the underlying molecular mechanism of radioresistance in ACP. EGFR activation promoting ACP cell survival and proliferation in vitro is consistent with enhanced survivin gene expression shown by qRT-PCR. TKI treatment, as well as the combination with radiotherapy, reduced survivin levels in vitro. Accordingly, ACP showed reduced cell viability and proliferation after survivin downregulation by siRNA. CONCLUSIONS These results indicate an impact of EGFR signaling on radioresistance in ACP. Inhibition of EGFR activity by means of TKI treatment acts as a radiosensitizer on ACP tumor cells, leading to increased cell death. Additionally, the results emphasize the antiapoptotic and pro-proliferative role of survivin in ACP biology and its regulation by EGFR signaling. The suppression of survivin by treatment with TKI and combined radiotherapy represents a new promising treatment strategy that will be further assessed in in vivo models of ACP.
机译：目的在这项研究中，作者研究了金刚放疗性颅咽管瘤（ACP）放疗后高肿瘤复发率的潜在机制，并开发了新的靶向治疗方案以最大程度地减少复发。 ACP的特征在于受体酪氨酸激酶表皮生长因子受体（EGFR）的激活，已知该受体在各种肿瘤实体中介导放射抗性。评估了酪氨酸激酶抑制剂（TKIs）吉非替尼或CUDC-101对辐射诱导的细胞死亡以及survivin基因表达的相关调节的影响。方法使用人原发性ACP细胞培养物（n = 10）在体外研究了激活EGFR促进ACP放射抵抗的假说。通过流式细胞术通过细胞死亡分析评估了放射线（12 Gy）和联合放化疗对放射敏感性的影响。通过定量实时聚合酶链反应（qRT-PCR）分析靶基因表达的变化。在qRT-PCR中鉴定出的Survivin与ACP的抗放射性有关，可通过小干扰RNA（siRNA）对其进行操纵，然后进行增殖和活力测定，以进一步阐明其在ACP生物学中的作用。在免疫组织化学上，在用于原代细胞培养的患者肿瘤中评估了survivin的表达。结果在原代人ACP培养物中，EGFR的激活导致放疗后细胞死亡水平显着降低。通过流式细胞术评估，单独使用TKI和联合放疗可显着提高细胞死亡反应。 CUDC-101比吉非替尼有效得多。作者将调节治疗后存活蛋白的表达确定为ACP放射抗性的潜在分子机制。 EGFR活化在体外促进ACP细胞存活和增殖与qRT-PCR显示的增强的survivin基因表达相一致。 TKI治疗以及放射治疗可降低体外生存素水平。因此，在siRNA使survivin下调后，ACP显示细胞活力和增殖降低。结论这些结果表明EGFR信号传导对ACP的放射抵抗具有影响。通过TKI处理抑制EGFR活性充当对ACP肿瘤细胞的放射增敏剂，导致细胞死亡增加。另外，结果强调了survivin在ACP生物学中的抗凋亡和增生作用及其通过EGFR信号传导的调控。通过TKI和放疗联合治疗抑制survivin代表了一种新的有希望的治疗策略，该策略将在ACP的体内模型中进一步评估。

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