Oncoprotein expression of E6 and E7 does not prevent 5-fluorouracil (5FU) mediated G1/S arrest and apoptosis in 5FU resistant carcinoma cell lines.
5-Fluorouracil (5FU) exposure can lead to both G1/S arrest and apoptosis induction which are dependent of P53 induction. The human papilloma virus oncoproteins (HPV), E6 and E7, inactivate respectively P53 and Rb. P53 degradation by E6 protein, leads to lack of G1/S arrest after genotoxic stress. Overexpression of E7 protein prevents P53-induced G1/S arrest following DNA damage. However, few studies have described 5FU effect and efficacy on cancer cell lines presenting HPV 18 positive status. KB cell line and KB3 subline presented wild-type P53 status and difference in 5FU sensitivity. During 5FU exposure, P53 gene and protein expression was increased in both cell lines. E6 and E7 mRNA and protein expression was decreased in KB and KB3. P53 and E6 protein expressions were inversely correlated. 5FU exposure, induced a G1/S arrest which can be maintained or intensified by P53 via P21 induction expression. 5FU exposure has led to apoptosis induction related to P53 induction. In the present study, 5FU exposure was shown to induce G1/S arrest and apoptosis by P53-dependent molecular pathway, in HPV 18 positive cells.
Didelot
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Centre Alexis Vautrin, Laboratoire de Recherche en Oncologie, Avenue de Bourgogne, 54511 Vandoeuvre-lès-Nancy Cedex, France.
Mirjolet
J-F
JF
Barberi-Heyob
M
M
Ramacci
C
C
Teiten
M-H
MH
Merlin
J L
JL
D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D016193:G1 Phase; D006801:Humans; D020128:Inhibitory Concentration 50; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins; D015513:Oncogene Proteins / Q000096:biosynthesis; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D012313:RNA; D004247:DNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D001973:Bromodeoxyuridine; D005472:Fluorouracil