Allen Christopher P, Tinganelli Walter, Sharma Neelam, Nie Jingyi, Sicard Cory, Natale Francesco, King Maurice, Keysar Steven B, Jimeno Antonio, Furusawa Yoshiya, Okayasu Ryuichi, Fujimori Akira, Durante Marco, Nickoloff Jac A
Department of Environmental and Radiological Health Sciences, Colorado State University , Fort Collins, CO , USA.
GSI Helmholtzzentrum für Schwerionenforschung GmbH , Darmstadt , Germany ; Research Development and Support Center, National Institute of Radiological Sciences , Chiba , Japan.
Front Oncol. 2015 Dec 7;5:260. doi: 10.3389/fonc.2015.00260. eCollection 2015.
Common cancer therapies employ chemicals or radiation that damage DNA. Cancer and normal cells respond to DNA damage by activating complex networks of DNA damage sensor, signal transducer, and effector proteins that arrest cell cycle progression, and repair damaged DNA. If damage is severe enough, the DNA damage response (DDR) triggers programed cell death by apoptosis or other pathways. Caspase 3 is a protease that is activated upon damage and triggers apoptosis, and production of prostaglandin E2 (PGE2), a potent growth factor that can enhance growth of surviving cancer cells leading to accelerated tumor repopulation. Thus, dying tumor cells can promote growth of surviving tumor cells, a pathway aptly named Phoenix Rising. In the present study, we surveyed Phoenix Rising responses in a variety of normal and established cancer cell lines, and in cancer cell lines freshly derived from patients. We demonstrate that IR induces a Phoenix Rising response in many, but not all cell lines, and that PGE2 production generally correlates with enhanced growth of cells that survive irradiation, and of unirradiated cells co-cultured with irradiated cells. We show that PGE2 production is stimulated by low and high LET ionizing radiation, and can be enhanced or suppressed by inhibitors of key DDR proteins. PGE2 is produced downstream of caspase 3 and the cyclooxygenases COX1 and COX2, and we show that the pan COX1-2 inhibitor indomethacin blocks IR-induced PGE2 production in the presence or absence of DDR inhibitors. COX1-2 require oxygen for catalytic activity, and we further show that PGE2 production is markedly suppressed in cells cultured under low (1%) oxygen concentration. Thus, Phoenix Rising is most likely to cause repopulation of tumors with relatively high oxygen, but not in hypoxic tumors. This survey lays a foundation for future studies to further define tumor responses to radiation and inhibitors of the DDR and Phoenix Rising to enhance the efficacy of radiotherapy with the ultimate goal of precision medicine informed by deep understanding of specific tumor responses to radiation and adjunct chemotherapy targeting key factors in the DDR and Phoenix Rising pathways.
常见的癌症治疗方法使用会损伤DNA的化学物质或辐射。癌症细胞和正常细胞通过激活由DNA损伤传感器、信号转导器和效应蛋白组成的复杂网络来应对DNA损伤，这些网络会使细胞周期进程停滞，并修复受损的DNA。如果损伤足够严重，DNA损伤反应（DDR）会通过凋亡或其他途径触发程序性细胞死亡。半胱天冬酶3是一种在损伤时被激活并触发凋亡的蛋白酶，同时还会产生前列腺素E2（PGE2），这是一种强大的生长因子，可促进存活癌细胞的生长，导致肿瘤再增殖加速。因此，垂死的肿瘤细胞可以促进存活肿瘤细胞的生长，这一途径被恰当地命名为“浴火重生”。在本研究中，我们调查了多种正常细胞系和已建立的癌细胞系以及从患者新鲜分离的癌细胞系中的“浴火重生”反应。我们证明，电离辐射（IR）在许多但并非所有细胞系中都会诱导“浴火重生”反应，并且PGE2的产生通常与受照射后存活的细胞以及与受照射细胞共培养的未受照射细胞的生长增强相关。我们表明，低线性能量传递（LET）和高线性能量传递的电离辐射都会刺激PGE2的产生，并且关键DDR蛋白的抑制剂可以增强或抑制这种产生。PGE2在半胱天冬酶3以及环氧化酶COX1和COX2的下游产生，并且我们表明，在存在或不存在DDR抑制剂的情况下，泛COX1-2抑制剂吲哚美辛都会阻断IR诱导的PGE2产生。COX1-2的催化活性需要氧气，并且我们进一步表明，在低氧（1%）浓度下培养的细胞中，PGE2的产生会明显受到抑制。因此，“浴火重生”最有可能导致相对高氧环境下肿瘤的再增殖，而在低氧肿瘤中则不会。这项调查为未来的研究奠定了基础，以便进一步确定肿瘤对辐射以及DDR和“浴火重生”抑制剂的反应，从而提高放射治疗的疗效，最终目标是通过深入了解特定肿瘤对辐射的反应以及针对DDR和“浴火重生”途径中的关键因素的辅助化疗来实现精准医学。
