R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways

Darrin M. Beaupre, Enrique Cepero, Esther A. Obeng, Lawrence H. Boise, Mathias G Lichtenheld

Research output: Contribution to journalArticle

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Abstract

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-XL 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.

Original languageEnglish
Pages (from-to)179-186
Number of pages8
JournalMolecular Cancer Therapeutics
Volume3
Issue number2
StatePublished - Feb 1 2004

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tipifarnib
Apoptosis
Endoplasmic Reticulum Stress
Caspase 9
Mitochondrial Membranes
Multiple Myeloma
Cell Death
Prenylation
Interleukin-6 Receptors
Transferases
Clinical Trials
Mutation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways. / Beaupre, Darrin M.; Cepero, Enrique; Obeng, Esther A.; Boise, Lawrence H.; Lichtenheld, Mathias G.

In: Molecular Cancer Therapeutics, Vol. 3, No. 2, 01.02.2004, p. 179-186.

Research output: Contribution to journalArticle

Beaupre, Darrin M. ; Cepero, Enrique ; Obeng, Esther A. ; Boise, Lawrence H. ; Lichtenheld, Mathias G. / R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways. In: Molecular Cancer Therapeutics. 2004 ; Vol. 3, No. 2. pp. 179-186.
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