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

In English

Författare

  • Sanna S. Virtanen
  • Jouko Sandholm
  • Gennady Yegutkin
  • H. Kalervo Vaananen
  • Pirkko Härkönen

Summary, in English

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.

Publiceringsår

2010

Språk

Engelska

Sidor

815-826

Publikation/Tidskrift/Serie

Cell Biology International

Volym

34

Issue

8

Dokumenttyp

Artikel i tidskrift

Förlag

Elsevier

Ämne

  • Cancer and Oncology

Nyckelord

  • actin cytoskeleton
  • cofilin
  • invasion
  • mevalonate pathway
  • prenyltransferase inhibitor
  • prostate cancer

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1095-8355