Department of Radiation Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Cancer Res. 2011 Nov 1;71(21):6817-26. doi: 10.1158/0008-5472.CAN-11-1646. Epub 2011 Sep 8.
Radiotherapy combined with androgen depletion is generally successful for treating locally advanced prostate cancer. However, radioresistance that contributes to recurrence remains a major therapeutic problem in many patients. In this study, we define the high-affinity neurotensin receptor 1 (NTR1) as a tractable new molecular target to radiosensitize prostate cancers. The selective NTR1 antagonist SR48692 sensitized prostate cancer cells in a dose- and time-dependent manner, increasing apoptotic cell death and decreasing clonogenic survival. The observed cancer selectivity for combinations of SR48692 and radiation reflected differential expression of NTR1, which is highly expressed in prostate cancer cells but not in normal prostate epithelial cells. Radiosensitization was not affected by androgen dependence or androgen receptor expression status. NTR1 inhibition in cancer cell-attenuated epidermal growth factor receptor activation and downstream signaling, whether induced by neurotensin or ionizing radiation, establish a molecular mechanism for sensitization. Most notably, SR48692 efficiently radiosensitized PC-3M orthotopic human tumor xenografts in mice, and significantly reduced tumor burden. Taken together, our findings offer preclinical proof of concept for targeting the NTR1 receptor as a strategy to improve efficacy and outcomes of prostate cancer treatments using radiotherapy.
放射治疗联合雄激素剥夺治疗通常可成功治疗局部晚期前列腺癌。然而，导致肿瘤复发的放射抵抗仍然是许多患者的主要治疗难题。在这项研究中，我们将高亲和力神经降压素受体 1（NTR1）定义为一种可行的新分子靶点，可使前列腺癌对放疗敏感。选择性 NTR1 拮抗剂 SR48692 以剂量和时间依赖的方式增敏前列腺癌细胞，增加细胞凋亡，降低克隆存活。观察到 SR48692 与放射联合使用的肿瘤选择性反映了 NTR1 的差异表达，NTR1 在前列腺癌细胞中高度表达，但在正常前列腺上皮细胞中不表达。NTR1 抑制对神经降压素或电离辐射诱导的表皮生长因子受体激活和下游信号没有影响，这为增敏作用建立了一个分子机制。值得注意的是，SR48692 可有效地增敏小鼠中 PC-3M 原位人肿瘤异种移植物的放射敏感性，并显著降低肿瘤负担。总之，我们的研究结果为靶向 NTR1 受体提供了临床前概念验证，可作为提高放疗治疗前列腺癌疗效和结果的一种策略。
