Radiation therapy is the primary intervention for nearly half of the patients with localized advanced prostate cancer and standard of care for recurrent disease following surgery. The development of radiation-resistant disease is an obstacle for nearly 30-50% of patients undergoing radiotherapy. A better understanding of mechanisms that lead to radiation resistance could aid in the development of sensitizing agents to improve outcome. Here we identified a radiation-resistance pathway mediated by CD105, downstream of BMP and TGF-β signaling. Antagonizing CD105-dependent BMP signaling with a partially humanized monoclonal antibody, TRC105, resulted in a significant reduction in clonogenicity when combined with irradiation. In trying to better understand the mechanism for the radio-sensitization, we found that radiation-induced CD105/BMP signaling was sufficient and necessary for the upregulation of sirtuin 1 (SIRT1) in contributing to p53 stabilization and PGC-1α activation. Combining TRC105 with irradiation delayed DNA damage repair compared to irradiation alone. However, in the absence of p53 function, combining TRC105 and radiation resulted in no reduction in clonogenicity compared to radiation alone, despite similar reduction of DNA damage repair observed in p53-intact cells. This suggested DNA damage repair was not the sole determinant of CD105 radio-resistance. As cancer cells undergo an energy deficit following irradiation, due to the demands of DNA and organelle repair, we examined SIRT1's role on p53 and PGC-1α with respect to glycolysis and mitochondrial biogenesis, respectively. Consequently, blocking the CD105-SIRT1 axis was found to deplete the ATP stores of irradiated cells and cause G2 cell cycle arrest. Xenograft models supported these findings that combining TRC105 with irradiation significantly reduces tumor size over irradiation alone (p value = 10^-9). We identified a novel synthetic lethality strategy of combining radiation and CD105 targeting to address the DNA repair and metabolic addiction induced by irradiation in p53-functional prostate cancers.

中文翻译：

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拮抗CD105可增强前列腺癌的放射敏感性。

放射治疗是将近一半的局限性晚期前列腺癌患者的主要干预措施，并且是术后复发疾病的标准治疗方法。抗辐射疾病的发展是将近30-50％接受放射治疗的患者的障碍。更好地理解导致辐射抗性的机制可能有助于开发敏化剂以改善治疗效果。在这里，我们确定了由CD105介导的BMP和TGF-β信号传导下游的抗辐射途径。与辐射结合时，用部分人源化的单克隆抗体TRC105拮抗CD105依赖性BMP信号导致克隆形成力的显着降低。为了更好地了解放射致敏机制，我们发现辐射诱导的CD105 / BMP信号传导对于sirtuin 1（SIRT1）的上调在p53稳定化和PGC-1α激活中的作用是必要的。与单独辐照相比，将TRC105与辐照结合可延迟DNA损伤修复。然而，在没有p53功能的情况下，与在单独的辐射中相比，将TRC105和辐射联合使用不会导致克隆形成性的降低，尽管在完整的p53细胞中观察到的DNA损伤修复也有类似的降低。这表明DNA损伤修复不是CD105放射抗性的唯一决定因素。由于DNA辐射和细胞器修复的需求，放射线照射后癌细胞会出现能量不足，因此，我们分别针对糖酵解和线粒体生物发生研究了SIRT1在p53和PGC-1α上的作用。所以，发现阻断CD105-SIRT1轴会耗尽辐照细胞的ATP储存，并导致G2细胞周期停滞。异种移植模型支持以下发现：与单独照射相比，TRC105与照射联合使用可显着减小肿瘤大小（p值= 10^-9）。我们确定了一种新颖的合成杀伤策略，将放射线和CD105靶向相结合，以解决在p53功能性前列腺癌中由放射线诱导的DNA修复和代谢成瘾。