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Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines.

Ageberg, Malin LU ; Fjordén, Karin LU ; Lindén, Ola LU ; Linderoth, Johan LU ; Jerkeman, Mats LU and Drott, Kristina LU (2011) In Experimental Cell Research 317. p.1179-1191
Abstract
Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line- based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitises DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor, FTI-277, or the... (More)
Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line- based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitises DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor, FTI-277, or the geranylgeranyl transferase I inhibitor, GGTI-298, indicates that the reduction in cell viability was restricted to inhibition of geranylgeranylation. In addition, treatment with BMS1, a combined inhibitor of farnesyl transferase and Rab GGT, resulted in a high cytostatic effect in WSU-NHL cells, demonstrated by reduced cell viability and decreased proliferation. Co-treatment of BMS1 or GGTI-298 with CHOP showed synergistic effects with regard to markers of apoptosis. We propose that inhibition of protein geranylgeranylation together with conventional cytostatic therapy is a potential novel strategy for treating patients with CHOP refractory DLBCL. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Cell Research
volume
317
pages
1179 - 1191
publisher
Academic Press
external identifiers
  • wos:000289336700009
  • pmid:21324313
  • scopus:79953100959
ISSN
1090-2422
DOI
10.1016/j.yexcr.2011.02.006
language
English
LU publication?
yes
id
2bad8a01-640a-4cfa-ad5a-8c70cd7ef201 (old id 1831790)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21324313?dopt=Abstract
date added to LUP
2011-03-01 15:34:32
date last changed
2017-08-27 05:43:14
@article{2bad8a01-640a-4cfa-ad5a-8c70cd7ef201,
  abstract     = {Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line- based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitises DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor, FTI-277, or the geranylgeranyl transferase I inhibitor, GGTI-298, indicates that the reduction in cell viability was restricted to inhibition of geranylgeranylation. In addition, treatment with BMS1, a combined inhibitor of farnesyl transferase and Rab GGT, resulted in a high cytostatic effect in WSU-NHL cells, demonstrated by reduced cell viability and decreased proliferation. Co-treatment of BMS1 or GGTI-298 with CHOP showed synergistic effects with regard to markers of apoptosis. We propose that inhibition of protein geranylgeranylation together with conventional cytostatic therapy is a potential novel strategy for treating patients with CHOP refractory DLBCL.},
  author       = {Ageberg, Malin and Fjordén, Karin and Lindén, Ola and Linderoth, Johan and Jerkeman, Mats and Drott, Kristina},
  issn         = {1090-2422},
  language     = {eng},
  pages        = {1179--1191},
  publisher    = {Academic Press},
  series       = {Experimental Cell Research},
  title        = {Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines.},
  url          = {http://dx.doi.org/10.1016/j.yexcr.2011.02.006},
  volume       = {317},
  year         = {2011},
}