Steroid-mediated inhibition of radiation-induced apoptosis in C4-1 cervical carcinoma cells is p53-dependent.
In human papillomavirus (HPV) infected cervical epithelial cells the synthetic steroid dexamethasone inhibits radiation-induced apoptosis and increases the transcription of HPV E6/E7, enhancing p53 degradation. The aim of this study was to determine if suppression of apoptosis was mechanistically linked to changes in p53. HPV 16 E6 or E6/E7 expression vectors were transiently transfected into C4-1 HPV 18-positive cervical carcinoma cells to mimic the enhanced transcription following steroid treatment. After irradiation, apoptosis was suppressed in these cells comparable to the effect observed after steroid treatment alone. To confirm whether loss of p53 was responsible for the inhibition of apoptosis, residual p53 in C4-1 cells was targeted by stable transfection with a dominant-negative p53 mutant. While radiation-induced apoptosis increased after mutant transfection, inhibition of programmed cell death by steroid treatment was either eliminated or substantially reduced. Steroid-dependent inhibition of radiation-induced apoptosis in carcinoma of the cervix involves E6 modulation of p53 expression and may adversely affect treatment.
Kamradt
M C
MC
Department of Cell Biology, Neurobiology and Anatomy, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Building 112, Room 332, 2160 South First Avenue, Maywood, IL 60153, USA.
Walter
S
S
Koudelik
J
J
Shafer
L
L
Weijzen
S
S
Velders
M
M
Vaughan
A T
AT
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D053938:DNA Fragmentation; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D027383:Papillomaviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology
D000893:Anti-Inflammatory Agents; D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone