Fan Yao, Fan Hui, Quan Zhen, Wu XiaoHou
Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Chongqing Medical University, Chongqing, China.
Cancer Invest. 2021 May;39(5):423-434. doi: 10.1080/07357907.2021.1899200. Epub 2021 Mar 24.
Tumor suppressor genes RB1 and TP53 are altered frequently in prostate cancer (PC), whether RB1 and TP53 inactivation promotes radioresistance remains unclear. Herein, we demonstrated that RB1 loss enhanced ionizing radiation (IR)-induced DNA damage to inhibit cell proliferation and promote cellular senescence through a TP53-dependent pathway in LNCaP cells. Furthermore, the stabilization of TP53 was regulated by ATM-mediated phosphorylation of MDM2 at Ser395. However, inactivation of RB1/TP53 reversed DNA damage-induced cellular senescence and promoted radiation survival. Importantly, combined with PARP1 inhibitor restored radiosensitivity. This finding provides a potential approach for the therapy of PC with RB1/TP53 inactivation.
肿瘤抑制基因RB1和TP53在前列腺癌（PC）中经常发生改变，RB1和TP53失活是否会促进放射抗性仍不清楚。在此，我们证明RB1缺失增强了电离辐射（IR）诱导的DNA损伤，通过LNCaP细胞中依赖TP53的途径抑制细胞增殖并促进细胞衰老。此外，TP53的稳定性由ATM介导的MDM2在Ser395位点的磷酸化调节。然而，RB1/TP53失活逆转了DNA损伤诱导的细胞衰老并促进了辐射存活。重要的是，与PARP1抑制剂联合使用可恢复放射敏感性。这一发现为治疗RB1/TP53失活的前列腺癌提供了一种潜在方法。
