Dual apoptotic effect of Xrel3 c‐Rel/NF‐κB homolog in human cervical cancer cells

AbstractCervical 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‐κB 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 μM 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 μM 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‐XL were elevated and the cell cycle regulator cyclin D1 was slightly upregulated with both 1 and 5 μM 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‐κB 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‐κB may potentially be of clinical significance in chemotherapy.