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PMID: 18787411 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation.

Cancer biology & therapy ·Vol. 7 ·No. 10 ·2008-10-00 ·Pages 1648-62

Park MA, Zhang G, Martin AP, Hamed H, Mitchell C, Hylemon PB, Graf M, Rahmani M, Ryan K, Liu X, Spiegel S, Norris J, Fisher PB, Grant S, Dent P

Abstract

We recently noted that low doses of sorafenib and vorinostat interact in a synergistic fashion to kill carcinoma cells by activating CD95, and this drug combination is entering phase I trials. The present studies mechanistically extended our initial observations. Low doses of sorafenib and vorinostat, but not the individual agents, caused an acidic sphingomyelinase and fumonisin B1-dependent increase in CD95 surface levels and CD95 association with caspase 8. Knock down of CD95 or FADD expression reduced sorafenib/vorinostat lethality. Signaling by CD95 caused PERK activation that was responsible for both promoting caspase 8 association with CD95 and for increased eIF2alpha phosphorylation; suppression of eIF2alpha function abolished drug combination lethality. Cell killing was paralleled by PERK-and eIF2alpha-dependent lowering of c-FLIP-s protein levels and overexpression of c-FLIP-s maintained cell viability. In a CD95-, FADD- and PERK-dependent fashion, sorafenib and vorinostat increased expression of ATG5 that was responsible for enhanced autophagy. Expression of PDGFRbeta and FLT3 were essential for high dose single agent sorafenib treatment to promote autophagy. Suppression of PERK function reduced sorafenib and vorinostat lethality whereas suppression of ATG5 levels elevated sorafenib and vorinostat lethality. Overexpression of c-FLIP-s blocked apoptosis and enhanced drug-induced autophagy. Thus sorafenib and vorinostat promote ceramide-dependent CD95 activation followed by induction of multiple downstream survival regulatory signals: ceramide-CD95-PERK-FADD-pro-caspase 8 (death); ceramide-CD95-PERK-eIF2alpha- downward arrowc-FLIP-s (death); ceramide-CD95-PERK-ATG5-autophagy (survival).

MeSH Terms
Antineoplastic Agents/pharmacology Autophagy Benzenesulfonates/pharmacology Caspase 8/metabolism Cell Survival Ceramides/metabolism Endoplasmic Reticulum/metabolism Eukaryotic Initiation Factor-2/metabolism Humans Hydroxamic Acids/pharmacology Models, Biological Mutation Niacinamide/analogs & derivatives Phenylurea Compounds Pyridines/pharmacology Sorafenib Treatment Outcome Vorinostat eIF-2 Kinase/biosynthesis fas Receptor/biosynthesis
Chemicals
Antineoplastic Agents Benzenesulfonates Ceramides Eukaryotic Initiation Factor-2 Hydroxamic Acids Phenylurea Compounds Pyridines fas Receptor Niacinamide Vorinostat Sorafenib PERK kinase eIF-2 Kinase Caspase 8
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Park Margaret A
Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
Zhang Guo
Martin Aditi Pandya
Hamed Hossein
Mitchell Clint
Hylemon Philip B
Graf Martin
Rahmani Mohamed
Ryan Kevin
Liu Xiang
Spiegel Sarah
Norris James
Fisher Paul B
Grant Steven
Dent Paul
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Article Info
Journal
Cancer biology & therapy
Abbr.
Cancer Biol Ther
ISSN
1555-8576
DOI
10.4161/cbt.7.10.6623
Published
2008-10-00
Epub
2008-00-12
Pages
1648-62
Language
English
Region
United States
NLM ID
101137842
PMCID
PMC2674577
Subset
IM
Grants
NCI NIH HHS · R01 CA108520 · United States
NCI NIH HHS · R01-CA77141 · United States
NCI NIH HHS · R01-CA63753 · United States
NCI NIH HHS · R01 CA063753 · United States
NIDDK NIH HHS · R01-DK52825 · United States
NCI NIH HHS · P01 CA104177 · United States
NIGMS NIH HHS · R37 GM043880-18 · United States
NIDDK NIH HHS · R01 DK052825 · United States
NCI NIH HHS · P01-CA104177 · United States
NCI NIH HHS · R01-CA108520 · United States
NCRR NIH HHS · C06 RR018823 · United States
NCRR NIH HHS · C06-RR018823 · United States
NCI NIH HHS · R01 CA061774 · United States
NIGMS NIH HHS · R37 GM043880 · United States
Corrections
CommentIn
PMID: 22095133
External Links
PubMed source DOI: 10.4161/cbt.7.10.6623 PMC Full Text View journal details
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