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 crucial in transduction of the apoptotic signal from CD95 to promote cell death. [Mol Cancer Ther 2008;7(9):2633–48]
- CD95
- caspase
- extrinsic
- FLIP
Footnotes
↵6 Supplementary materials for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
↵7 Unpublished findings.
Grant support: USPHS grants R01-DK52825, P01-CA104177, and R01-CA108325 and The Jim Valvano “V” Foundation (P. Dent); USPHS grants R01-CA63753 and R01-CA77141 and Leukemia Society of America grant 6405-97 (S. Grant); USPHS grants P01-CA104177, R01-CA097318, R01-CA098172, and P01-NS031492 and The Samuel Waxman Cancer Research Foundation (P.B. Fisher); and USPHS grant P01-CA104177 (D.T. Curiel). P. Dent is The Universal, Inc., Professor in Signal Transduction Research and P.B. Fisher is a Samuel Waxman Cancer Research Foundation investigator.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: M.A. Park and G. Zhang contributed equally to the execution and completion of these studies.
- Accepted June 9, 2008.
- Received April 24, 2008.
- Revision received June 9, 2008.
- American Association for Cancer Research
Volume 7, Issue 9
