Inhibition of neurotensin receptor 1 selectively sensitizes prostate cancer to ionizing radiation.
Inhibition of neurotensin receptor 1 selectively sensitizes prostate cancer to ionizing radiation.
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DOI：
10.1158/0008-5472.can-11-1646
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发表时间：
2011-09
期刊：
影响因子：
11.2
通讯作者：
Nicholas C. K. Valerie;E. Casarez;J. DaSilva;M. Dunlap-Brown;S. Parsons;G. Amorino;J. Dziegielewski
中科院分区：
文献类型：
--
作者：
Nicholas C. K. Valerie;E. Casarez;J. DaSilva;M. Dunlap-Brown;S. Parsons;G. Amorino;J. Dziegielewski
放射治疗结合雄激素耗竭治疗局部晚期前列腺癌通常是成功的。然而，导致复发的放射抵抗仍然是许多患者的主要治疗问题。在这项研究中，我们将高亲和力神经降压素受体1(NTR1)定义为一个易于处理的新分子靶点，用于前列腺癌的放射增敏。选择性的NTR1拮抗剂SR48692以剂量和时间依赖的方式敏化前列腺癌细胞，增加凋亡细胞的死亡，降低克隆形成的存活率。观察到的SR48692和辐射组合的癌症选择性反映了NTR1的不同表达，NTR1在前列腺癌细胞中高表达，但在正常前列腺上皮细胞中不表达。放射增敏不受雄激素依赖或雄激素受体表达状态的影响。NTR1抑制癌细胞--减弱表皮生长因子受体的激活和下游信号，无论是由神经降压素还是电离辐射诱导，都建立了致敏的分子机制。最值得注意的是，SR48692有效地增敏了PC-3M小鼠原位人肿瘤移植瘤，并显著降低了肿瘤负担。综上所述，我们的发现为靶向NTR1受体作为一种策略来提高前列腺癌放射治疗的疗效和结果的临床前概念提供了证据。
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.