title: Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95.
abstract: Prior studies have noted that inhibitors of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) enhanced geldanamycin lethality in malignant hematopoietic cells by promoting mitochondrial dysfunction. The present studies focused on defining the mechanism(s) by which these agents altered survival in carcinoma cells. MEK1/2 inhibitors [PD184352; AZD6244 (ARRY-142886)] interacted in a synergistic manner with geldanamycins [17-allylamino-17-demethoxygeldanamycin (17AAG) and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin] to kill hepatoma and pancreatic carcinoma cells that correlated with inactivation of extracellular signal-regulated kinase 1/2 and AKT and with activation of p38 MAPK; p38 MAPK activation was reactive oxygen species dependent. Treatment of cells with MEK1/2 inhibitors and 17AAG reduced expression of c-FLIP-s that was mechanistically connected to loss of MEK1/2 and AKT function; inhibition of caspase-8 or overexpression of c-FLIP-s abolished cell killing by MEK1/2 inhibitors and 17AAG. Treatment of cells with MEK1/2 inhibitors and 17AAG caused a p38 MAPK-dependent plasma membrane clustering of CD95 without altering the levels or cleavage of FAS ligand. In parallel, treatment of cells with MEK1/2 inhibitors and 17AAG caused a p38 MAPK-dependent association of caspase-8 with CD95. Inhibition of p38 MAPK or knockdown of BID, FAS-associated death domain, or CD95 expression suppressed MEK1/2 inhibitor and 17AAG lethality. Similar correlative data were obtained using a xenograft flank tumor model system. Our data show that treatment of tumor cells with MEK1/2 inhibitors and 17AAG induces activation of the extrinsic pathway and that suppression of c-FLIP-s expression is [Mol Cancer Ther 2008;7(9):2633-48].
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, 401 College Street, Massey Cancer Center, Box 980035, Richmond, VA 23298-0035, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Park
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang
authors.forename: Clint
authors.initials: C
authors.lastname: Mitchell
authors.forename: Mohamed
authors.initials: M
authors.lastname: Rahmani
authors.forename: Hossein
authors.initials: H
authors.lastname: Hamed
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hagan
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D019014:fas Receptor; C112765:tanespimycin; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
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