Cilensek Zoran M, Yehiely Fruma, Kular Rupinder K, Deiss Louis P
Department of Molecular Genetics, University of Illinois at Chicago, 60607, USA.
Cancer Biol Ther. 2002 Jul-Aug;1(4):380-7.
Attractive targets for cancer therapy are gene products whose inactivation is not detrimental in essential tissues. The GAGE family of Cancer/Testis Antigens is a group of appealing candidates for cancer therapy since they are expressed in a wide variety of human tumors and are silent in most adult tissues, with the exception of testis. Interestingly, expression of GAGE has been associated with poor prognosis in some cancers. Nevertheless, no function has been reported for any of the GAGE family members. Here we describe for the first time an anti-apoptotic activity exerted by GAGE. We have cloned GAGE-7C from HeLa cells and showed that it renders transfected cells resistant to apoptosis induced by Interferon-gamma (IFN-gamma) or by the death receptor Fas/CD95/APO-1. Similarly, transfection of GAGE-7/7B also confers resistance to Fas induced apoptosis. In the Fas pathway, the anti-apoptotic activity of GAGE-7C maps downstream of caspase-8 activation and upstream of poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore, GAGE-7C renders the cells resistant to the therapeutic agents Taxol and gamma-irradiation. Following the various apoptotic stimuli, the surviving GAGE-7C transfectants actively proliferate and exhibit enhanced long term survival in colony formation assays. Overall, our data establishes a functional link between GAGE-7C and two aspects of human tumor progression; namely, resistance to Fas induced apoptosis and to chemo- and radio-therapy.
癌症治疗的有吸引力的靶点是那些在重要组织中失活不会产生有害影响的基因产物。癌症/睾丸抗原的GAGE家族是癌症治疗中一组有吸引力的候选对象，因为它们在多种人类肿瘤中表达，而在除睾丸外的大多数成人组织中沉默。有趣的是，GAGE的表达在某些癌症中与预后不良有关。然而，尚未报道任何GAGE家族成员的功能。在此，我们首次描述了GAGE发挥的抗凋亡活性。我们从HeLa细胞中克隆了GAGE-7C，并表明它使转染细胞对干扰素-γ（IFN-γ）或死亡受体Fas/CD95/APO-1诱导的凋亡具有抗性。同样，转染GAGE-7/7B也赋予对Fas诱导凋亡的抗性。在Fas途径中，GAGE-7C的抗凋亡活性定位于半胱天冬酶-8激活的下游和聚（ADP-核糖）聚合酶（PARP）裂解的上游。此外，GAGE-7C使细胞对治疗药物紫杉醇和γ射线辐射具有抗性。在各种凋亡刺激后，存活的GAGE-7C转染细胞积极增殖，并在集落形成试验中表现出增强的长期存活能力。总体而言，我们的数据在GAGE-7C与人类肿瘤进展的两个方面之间建立了功能联系；即对Fas诱导凋亡以及化疗和放疗的抗性。
