Dual apoptotic effect of Xrel3 c-Rel/NF-kappaB homolog in human cervical cancer cells.
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.
Shehata
Marlene
M
Division of Basic Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada A1B 3V6. mshehata@ottawaheart.ca
Shehata
Marian
M
Shehata
Fady
F
Pater
Alan
A
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000187:drug effects / Q000235:genetics*; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D029867:Xenopus Proteins; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C091732:BCL2-associated athanogene 1 protein; C494811:BCL2L1 protein, human; C493956:CDKN1A protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D020569:Proto-Oncogene Proteins c-rel; D014157:Transcription Factors; D029867:Xenopus Proteins; D051020:bcl-X Protein; C500754:rel3 protein, Xenopus; D019938:Cyclin D1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D002945:Cisplatin