Shehata Marlene, Shehata Marian, Shehata Fady, Pater Alan
Division of Basic Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada A1B 3V6.
Cell Biol Int. 2004;28(12):895-904. doi: 10.1016/j.cellbi.2004.09.002.
Cervical cancer is one of the most common cancers affecting a woman's reproductive organs. Despite its frequency and recurrence, the death rate has been declining over the past 40 years, due to early detection and treatment. In a previous report [Shehata Marlene, Shehata Marian, Shehata Fady, Pater Alan. Apoptosis effects of Xrel3 c-Rel/Nuclear factor-kappa B homolog in human cervical cancer cells. Cell Biology International, in press], we studied the role of the NF-kappaB gene family in HeLa human cervical cancer cells, using the Xrel3 c-Rel homologue of Xenopus laevis. These results showed that the expression of Xrel3/c-Rel slowed cell growth, consistent with an upregulated expression of the cell cycle inhibitor p21 and the activated poly(ADP-ribose) polymerase (PARP) apoptosis effector. However, in this report, we examined more apoptotic and anti-apoptotic factors acting upstream and downstream in apoptosis pathways after cisplatin treatment of HeLa cervical cancer cells. After 1 microM cisplatin treatment, Xrel3 had an anti-apoptotic effect, based on significantly lower levels of apoptotic proteins, including caspase-8, caspase-3 and p21. Anti-apoptotic BAG-1 isoforms were upregulated. After 5 microM cisplatin treatment, expression of HeLa Xrel3 had an apoptotic effect, based on significantly increased expression of the cell cycle inhibitor p21 and apoptotic proteins, including cleaved PARP, caspase-8, and caspase-3. However, anti-apoptotic Bcl-2 and Bcl-X(L) were elevated and the cell cycle regulator cyclin D1 was slightly upregulated with both 1 and 5 microM cisplatin treatment. The HPV E6 oncoprotein showed no significant changes. These results support previous conclusions on the potential anti-apoptotic effects of c-Rel/NF-kappaB in mild stress environments, as opposed to the apoptotic effects associated with high stress conditions [Lake BB, Ford R, Kao KR. Xrel3 is required for head development in Xenopus laevis. Development 2001; 128(2), 263-73.]. Thus, c-Rel/NF-kappaB may potentially be of clinical significance in chemotherapy.
宫颈癌是影响女性生殖器官的最常见癌症之一。尽管其发病率和复发率较高，但由于早期发现和治疗，在过去40年里死亡率一直在下降。在之前的一份报告中[谢哈塔·玛琳、谢哈塔·玛丽安、谢哈塔·法迪、佩特·艾伦。Xrel3 c-Rel/核因子-κB同源物对人宫颈癌细胞凋亡的影响。《细胞生物学国际》，即将发表]，我们利用非洲爪蟾的Xrel3 c-Rel同源物研究了NF-κB基因家族在HeLa人宫颈癌细胞中的作用。这些结果表明，Xrel3/c-Rel的表达减缓了细胞生长，这与细胞周期抑制剂p21的表达上调以及活化的聚（ADP-核糖）聚合酶（PARP）凋亡效应器一致。然而，在本报告中，我们检测了顺铂处理HeLa宫颈癌细胞后，凋亡途径上下游更多的凋亡和抗凋亡因子。用1微摩尔顺铂处理后，基于凋亡蛋白（包括半胱天冬酶-8、半胱天冬酶-3和p21）水平显著降低，Xrel3具有抗凋亡作用。抗凋亡BAG-1亚型上调。用5微摩尔顺铂处理后，基于细胞周期抑制剂p21和凋亡蛋白（包括裂解的PARP、半胱天冬酶-8和半胱天冬酶-3）的表达显著增加，HeLa Xrel3的表达具有凋亡作用。然而，用1微摩尔和5微摩尔顺铂处理后，抗凋亡蛋白Bcl-2和Bcl-X(L)升高，细胞周期调节因子细胞周期蛋白D1略有上调。人乳头瘤病毒E6癌蛋白无显著变化。这些结果支持了之前关于c-Rel/NF-κB在轻度应激环境中潜在抗凋亡作用的结论，这与高应激条件下的凋亡作用相反[莱克BB、福特R、考KR。非洲爪蟾头部发育需要Xrel3。《发育》2001年；128(2)，263 - 273]。因此，c-Rel/NF-κB在化疗中可能具有潜在的临床意义。
