title: Cytotoxic drug-induced, p53-mediated upregulation of caspase-8 in tumor cells.
abstract: Apoptosis resistance is crucially involved in cancer development and progression, represents the leading cause for failure of anticancer therapy and is caused, for example, by downregulation of proapoptotic intracellular signaling molecules such as caspase-8. We found that the cytotoxic drugs methotrexate (MTX) and 5-fluorouracil (5-FU) were both able to sensitize resistant tumor cells for induction of apoptosis by p53-mediated upregulation of caspase-8. Increase in caspase-8 messenger RNA and protein expression disabled tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced proliferation and restored sensitivity toward TRAIL-induced apoptosis which was inhibited by transfection of p53 decoy oligonucleotides, p53 shRNA and caspase-8 shRNA. Upregulation of caspase-8 and sensitization toward TRAIL-induced apoptosis was found both in a broad panel of tumor cell lines with downregulated caspase-8 and in TRAIL-resistant primary tumor cells of children with acute leukemia. Taken together, we have identified caspase-8 as an important p53 target gene regulated by cytotoxic drugs. These findings highlight a new drug-induced modulation of physiological apoptosis pathways, which may be involved in successful anticancer therapy using MTX and 5-FU in leukemia and solid tumors over decades.
authors.affiliation: Department of Oncology/Hematology, Dr von Haunersches Kinderspital, München, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Ehrhardt
authors.forename: S
authors.initials: S
authors.lastname: Häcker
authors.forename: S
authors.initials: S
authors.lastname: Wittmann
authors.forename: M
authors.initials: M
authors.lastname: Maurer
authors.forename: A
authors.initials: A
authors.lastname: Borkhardt
authors.forename: A
authors.initials: A
authors.lastname: Toloczko
authors.forename: K-M
authors.initials: KM
authors.lastname: Debatin
authors.forename: S
authors.initials: S
authors.lastname: Fulda
authors.forename: I
authors.initials: I
authors.lastname: Jeremias
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D053181:Caspase 8; D005472:Fluorouracil; D008727:Methotrexate