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Inhibition of GGTase-I and FTase disrupts cytoskeletal organization of human PC-3 prostate cancer cells

Virtanen, Sanna S.; Sandholm, Jouko; Yegutkin, Gennady; Vaananen, H. Kalervo and Härkönen, Pirkko LU (2010) In Cell Biology International 34(8). p.815-826
Abstract
The mevalonate synthesis pathway produces intermediates for isoprenylation of small GTPases, which are involved in the regulation of actin cytoskeleton and cell motility. Here, we investigated the role of the prenylation transferases in the regulation of the cytoskeletal organization and motility of PC-3 prostate cancer cells. This was done by using FTI-277, GGTI-298 or NE-10790, the specific inhibitors of FTase (farnesyltransferase), GGTase (geranylgeranyltransferase)-I and -II, respectively. Treatment of PC-3 cells with GGTI-298 and FTI-277 inhibited migration and invasion in a time- and dose-dependent manner. This was associated with disruption of F-actin organization and decreased recovery of GFP-actin. Immunoblot analysis of various... (More)
The mevalonate synthesis pathway produces intermediates for isoprenylation of small GTPases, which are involved in the regulation of actin cytoskeleton and cell motility. Here, we investigated the role of the prenylation transferases in the regulation of the cytoskeletal organization and motility of PC-3 prostate cancer cells. This was done by using FTI-277, GGTI-298 or NE-10790, the specific inhibitors of FTase (farnesyltransferase), GGTase (geranylgeranyltransferase)-I and -II, respectively. Treatment of PC-3 cells with GGTI-298 and FTI-277 inhibited migration and invasion in a time- and dose-dependent manner. This was associated with disruption of F-actin organization and decreased recovery of GFP-actin. Immunoblot analysis of various cytoskeleton-associated proteins showed that the most striking change in GGTI-298- and FTI-277-treated cells was a markedly decreased level of total and phosphorylated cofilin, whereas the level of cofilin mRNA was not decreased. The treatment of PC-3 cells with GGTI-298 also affected the dynamics of GFP-paxillin and decreased the levels of total and phosphorylated paxillin. The levels of phosphorylated FAK (focal adhesion kinase) and PAK (p-21-associated kinase)-2 were also lowered by GGTI-298, but levels of paxillin or FAK mRNAs were not affected. In addition, GGTI-298 had a minor effect on the activity of MMP-9. RNAi knockdown of GGTase-I beta inhibited invasion, disrupted F-actin organization and decreased the level of cofilin in PC-3 cells. NE-10790 did not have any effect on PC-3 prostate cancer cell motility or on the organization of the cytoskeleton. In conclusion, our results demonstrate the involvement of GGTase-I- and FTase-catalysed prenylation reactions in the regulation of cytoskeletal integrity and motility of prostate cancer cells and suggest them as interesting drug targets for development of inhibitors of prostate cancer metastasis. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
actin cytoskeleton, cofilin, invasion, mevalonate pathway, prenyltransferase inhibitor, prostate cancer
in
Cell Biology International
volume
34
issue
8
pages
815 - 826
publisher
Elsevier
external identifiers
  • wos:000288641000005
  • scopus:77956108573
ISSN
1095-8355
DOI
10.1042/CBI20090288
language
English
LU publication?
yes
id
98ab6ea2-b4a0-4272-8a9c-93f5ed8526fe (old id 1918182)
date added to LUP
2011-05-03 08:21:41
date last changed
2018-05-29 09:21:13
@article{98ab6ea2-b4a0-4272-8a9c-93f5ed8526fe,
  abstract     = {The mevalonate synthesis pathway produces intermediates for isoprenylation of small GTPases, which are involved in the regulation of actin cytoskeleton and cell motility. Here, we investigated the role of the prenylation transferases in the regulation of the cytoskeletal organization and motility of PC-3 prostate cancer cells. This was done by using FTI-277, GGTI-298 or NE-10790, the specific inhibitors of FTase (farnesyltransferase), GGTase (geranylgeranyltransferase)-I and -II, respectively. Treatment of PC-3 cells with GGTI-298 and FTI-277 inhibited migration and invasion in a time- and dose-dependent manner. This was associated with disruption of F-actin organization and decreased recovery of GFP-actin. Immunoblot analysis of various cytoskeleton-associated proteins showed that the most striking change in GGTI-298- and FTI-277-treated cells was a markedly decreased level of total and phosphorylated cofilin, whereas the level of cofilin mRNA was not decreased. The treatment of PC-3 cells with GGTI-298 also affected the dynamics of GFP-paxillin and decreased the levels of total and phosphorylated paxillin. The levels of phosphorylated FAK (focal adhesion kinase) and PAK (p-21-associated kinase)-2 were also lowered by GGTI-298, but levels of paxillin or FAK mRNAs were not affected. In addition, GGTI-298 had a minor effect on the activity of MMP-9. RNAi knockdown of GGTase-I beta inhibited invasion, disrupted F-actin organization and decreased the level of cofilin in PC-3 cells. NE-10790 did not have any effect on PC-3 prostate cancer cell motility or on the organization of the cytoskeleton. In conclusion, our results demonstrate the involvement of GGTase-I- and FTase-catalysed prenylation reactions in the regulation of cytoskeletal integrity and motility of prostate cancer cells and suggest them as interesting drug targets for development of inhibitors of prostate cancer metastasis.},
  author       = {Virtanen, Sanna S. and Sandholm, Jouko and Yegutkin, Gennady and Vaananen, H. Kalervo and Härkönen, Pirkko},
  issn         = {1095-8355},
  keyword      = {actin cytoskeleton,cofilin,invasion,mevalonate pathway,prenyltransferase inhibitor,prostate cancer},
  language     = {eng},
  number       = {8},
  pages        = {815--826},
  publisher    = {Elsevier},
  series       = {Cell Biology International},
  title        = {Inhibition of GGTase-I and FTase disrupts cytoskeletal organization of human PC-3 prostate cancer cells},
  url          = {http://dx.doi.org/10.1042/CBI20090288},
  volume       = {34},
  year         = {2010},
}