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: Margaret A Park, Guo Zhang, Clint Mitchell, Mohamed Rahmani, Hossein Hamed, Michael P Hagan, Adly Yacoub, David T Curiel, Paul B Fisher, Steven Grant, Paul Dent
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 9 Pg. 2633-48 (Sep 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18790746 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Benzoquinones
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Lactams, Macrocyclic
• Protein Kinase Inhibitors
• Reactive Oxygen Species
• fas Receptor
• tanespimycin
• Proto-Oncogene Proteins c-akt
• p38 Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Apoptosis Regulatory Proteins (metabolism)
• Benzoquinones (pharmacology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Carcinoma, Hepatocellular (enzymology, pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Drug Synergism
• Enzyme Activation (drug effects)
• Female
• Gastrointestinal Neoplasms (enzymology, pathology)
• Humans
• Lactams, Macrocyclic (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Mice
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Xenograft Model Antitumor Assays
• fas Receptor (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)