title: The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress.
abstract: Sorafenib is a multikinase inhibitor that induces apoptosis in human leukemia and other malignant cells. Recently, we demonstrated that sorafenib diminishes Mcl-1 protein expression by inhibiting translation through a MEK1/2-ERK1/2 signaling-independent mechanism and that this phenomenon plays a key functional role in sorafenib-mediated lethality. Here, we report that inducible expression of constitutively active MEK1 fails to protect cells from sorafenib-mediated lethality, indicating that sorafenib-induced cell death is unrelated to MEK1/2-ERK1/2 pathway inactivation. Notably, treatment with sorafenib induced endoplasmic reticulum (ER) stress in human leukemia cells (U937) manifested by immediate cytosolic-calcium mobilization, GADD153 and GADD34 protein induction, PKR-like ER kinase (PERK) and eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation, XBP1 splicing, and a general reduction in protein synthesis as assessed by [35S]methionine incorporation. These events were accompanied by pronounced generation of reactive oxygen species through a mechanism dependent upon cytosolic-calcium mobilization and a significant decline in GRP78/Bip protein levels. Interestingly, enforced expression of IRE1alpha markedly reduced sorafenib-mediated apoptosis, whereas knockdown of IRE1alpha or XBP1, disruption of PERK activity, or inhibition of eIF2alpha phosphorylation enhanced sorafenib-mediated lethality. Finally, downregulation of caspase-2 or caspase-4 by small interfering RNA significantly diminished apoptosis induced by sorafenib. Together, these findings demonstrate that ER stress represents a central component of a MEK1/2-ERK1/2-independent cell death program triggered by sorafenib.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, MCV Station Box 230, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Rahmani
authors.forename: Eric Maynard
authors.initials: EM
authors.lastname: Davis
authors.forename: Timothy Ryan
authors.initials: TR
authors.lastname: Crabtree
authors.forename: Joseph Reza
authors.initials: JR
authors.lastname: Habibi
authors.forename: Tri K
authors.initials: TK
authors.lastname: Nguyen
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D053143:Caspase 2 / Q000378:metabolism; D053471:Caspases, Initiator / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D009687:Nuclear Proteins / Q000378:metabolism; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012326:RNA Splicing / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D000077157:Sorafenib; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001557:Benzenesulfonates; D053143:Caspase 2; D053471:Caspases, Initiator; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D009536:Niacinamide; D009687:Nuclear Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D000077157:Sorafenib; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C093516:CASP4 protein, human