Effect of p53 status and STAT1 on chemotherapy-induced, Fas-mediated apoptosis in colorectal cancer.
We investigated the role of p53 and the signal transducer and activator of transcription 1 (STAT1) in regulating Fas-mediated apoptosis in response to chemotherapies used to treat colorectal cancer. We found that 5-fluorouracil (5-FU) and oxaliplatin only sensitized p53 wild-type (WT) colorectal cancer cell lines to Fas-mediated apoptosis. In contrast, irinotecan (CPT-11) and tomudex sensitized p53 WT, mutant, and null cells to Fas-mediated cell death. Furthermore, CPT-11 and tomudex, but not 5-FU or oxaliplatin, up-regulated Fas cell surface expression in a p53-independent manner. In addition, increased Fas cell surface expression in p53 mutant and null cell lines in response to CPT-11 and tomudex was accompanied by only a slight increase in total Fas mRNA and protein expression, suggesting that these agents trigger p53-independent trafficking of Fas to the plasma membrane. Treatment with CPT-11 or tomudex induced STAT1 phosphorylation (Ser727) in the p53-null HCT116 cell line but not the p53 WT cell line. Furthermore, STAT1-targeted small interfering RNA (siRNA) inhibited up-regulation of Fas cell surface expression in response to CPT-11 and tomudex in these cells. However, we found no evidence of altered Fas gene expression following siRNA-mediated down-regulation of STAT1 in drug-treated cells. This suggests that STAT1 regulates expression of gene(s) involved in cell surface trafficking of Fas in response to CPT-11 or tomudex. We conclude that CPT-11 and tomudex may be more effective than 5-FU and oxaliplatin in the treatment of p53 mutant colorectal cancer tumors by sensitizing them to Fas-mediated apoptosis in a STAT1-dependent manner.
McDermott
Ultan
U
Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
Longley
Daniel B
DB
Galligan
Leeona
L
Allen
Wendy
W
Wilson
Timothy
T
Johnston
Patrick G
PG
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D000911:Antibodies, Monoclonal; D009944:Organoplatinum Compounds; D011799:Quinazolines; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495901:TP53 protein, human; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D000077150:Oxaliplatin; D000077146:Irinotecan; C068874:raltitrexed; D005472:Fluorouracil; D002166:Camptothecin