R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways.
Ras activation is frequently observed in multiple myeloma either by mutation or through interleukin-6 receptor signaling. Recently, drugs designed to inhibit Ras have shown promise in preclinical myeloma models and in clinical trials. In this report, we characterize the pathways by which the clinically tested farnesyl transferase inhibitor (FTI) R115777 induces apoptosis in multiple myeloma cells. Contrary to the proposed mechanistic action of FTIs, we found that R115777 induces cell death despite Ras prenylation implying participation of Ras-independent mechanism(s). Apoptosis proceeded via an intrinsic cascade and was associated with an increase in the expression and activity of Bax. Bax activation correlated with a loss of mitochondrial membrane integrity and activation of the endoplasmic reticulum (ER) stress response. These pathways activate caspase-9 and consistent with this, cell death was prevented by caspase-9 blockade. Interestingly, cells overexpressing Bcl-X(L) remained partially sensitive to R115777 despite suppression of mitochondrial membrane dysfunction and ER-related stress. Taken together, these results indicate that R115777 induces apoptosis in a Ras-independent fashion via multiple intrinsic pathways.
Beaupre
Darrin M
DM
Department of Medicine, Division of Hematology and Oncology, Sylvester Cancer Center, University of Miami School of Medicine, Miami, FL, USA.
Cepero
Enrique
E
Obeng
Esther A
EA
Boise
Lawrence H
LH
Lichtenheld
Mathias G
MG
D017209:Apoptosis / Q000187:drug effects*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015363:Quinolones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D018631:ras Proteins / Q000378:metabolism*
C494772:BAK1 protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; D061945:Caspase Inhibitors; C497249:DDIT3 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C485722:NPBWR1 protein, human; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015363:Quinolones; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D051742:Transcription Factor CHOP; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D018631:ras Proteins; C402769:tipifarnib