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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-58157

Wu, J; Wong, W. Wei-Lynn; Khosravi, F; Minden, M; Penn, L Z (2004). Blocking the Raf/MEK/ERK Pathway Sensitizes Tumor Cells to Lovastatin-Induced Apoptosis. Cancer Research, 64:6461-6468.

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Abstract

The statin family of drugs are well-established inhibitors of 3-hydroxy-
3-methylglutaryl-CoA reductase and are used clinically in the control of
hypercholesterolemia. Recent evidence, from ourselves and others, shows
that statins can also trigger tumor-specific apoptosis by blocking protein
geranylgeranylation. We and others have proposed that statins disrupt
localization and function of geranylgeranylated proteins responsible for
activating signal transduction pathways essential for the growth and/or
survival of transformed cells. To explore this further, we have investigated
whether the mitogen-activated protein kinase (MAPK) signaling cascades
play a role in regulating statin-induced apoptosis. Cells derived from acute
myelogenous leukemia (AML) are used as our model system. We show
that p38 and c-Jun NH2-terminal kinase/stress-activated kinase MAPK
pathways are not altered during lovastatin-induced apoptosis. By contrast,
exposure of primary and established AML cells to statins results in
significant disruption of basal extracellular signal-regulated kinase (ERK)
1/2 phosphorylation. Addition of geranylgeranyl PPi reverses statininduced
loss of ERK1/2 phosphorylation and apoptosis. By establishing
and evaluating the inducible Raf-1:ER system in AML cells, we show that
constitutive activation of the Raf/MAPK kinase (MEK)/ERK pathway
significantly represses but does not completely block lovastatin-induced
apoptosis. Our results strongly suggest statins trigger apoptosis by regulating
several signaling pathways, including the Raf/MEK/ERK pathway.
Indeed, down-regulation of the Raf/MEK/ERK pathway potentiates
statin-induced apoptosis because exposure to the MEK1 inhibitor
PD98059 sensitizes AML cells to low, physiologically achievable concentrations
of lovastatin. Our study suggests that lovastatin, alone or in
combination with a MEK1 inhibitor, may represent a new and immediately
available therapeutic approach to combat tumors with activated
ERK1/2, such as AML.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Experimental Immunology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2004
Deposited On:19 Jun 2012 13:35
Last Modified:15 Dec 2013 06:29
Publisher:American Association for Cancer Research
ISSN:0008-5472
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1158/0008-5472.CAN-04-0866
Citations:Web of Science®. Times Cited: 115
Google Scholar™
Scopus®. Citation Count: 126

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