The interaction of thymidylate synthase expression with p53-regulated signaling pathways in tumor cells.
Thymidylate synthase (TS) is a chemotherapeutic target for the fluoropyrimidine 5-fluorouracil (5-FU) and antifolate tomudex (TDX). Using the MCF-7 breast cancer line, we have developed a cell line with inducible TS expression termed M7TS90. Inducible TS expression in this line resulted in a moderate (approximately 3-fold) increase in 5-FU 50% inhibitory concentration at 72 hours (IC-50(72 h)) dose and a dramatic (approximately 24-fold) increase in the IC-50(72 h) dose of TDX, but did not affect chemosensitivity to cisplatin, oxaliplatin, irinotecan, and paclitaxel. In the absence of drug treatment, inducible TS expression had no effect on expression of the p53 tumor suppressor gene. However, TS induction abrogated p53, p21, Fas, and Bak induction in response to TDX, but not 5-FU. Similarly, downregulation of Bcl-2 was reversed by inducible TS expression in TDX, but not 5-FU-treated cells. Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX, but not 5-FU.
Longley
Daniel B
DB
Cancer Research Centre, Queen's University Belfast, Belfast, Northern Ireland.
Latif
Tariq
T
Boyer
John
J
Allen
Wendy L
WL
Maxwell
Pamela J
PJ
Johnston
Patrick G
PG
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015398:Signal Transduction; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase