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Clinical & Experimental Metastasis

, Volume 28, Issue 5, pp 479–491 | Cite as

Impact of combined HDAC and mTOR inhibition on adhesion, migration and invasion of prostate cancer cells

  • Steffen Wedel
  • Lukasz Hudak
  • Jens-Michael Seibel
  • Jasmina Makarević
  • Eva Juengel
  • Igor Tsaur
  • Christoph Wiesner
  • Axel Haferkamp
  • Roman A. Blaheta
Research Paper

Abstract

The concept of molecular tumor targeting might provide new hope in the treatment of advanced prostate cancer. We evaluated metastasis blocking properties of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell lines. RAD001 or VPA were applied to PC-3 or LNCaP cells, either separately or in combination. Adhesion to vascular endothelium or to immobilized collagen, fibronectin or laminin was quantified. Migration and invasion were explored by a modified Boyden chamber assay. Integrin α and β subtypes were analyzed by flow cytometry, western blotting and RT-PCR. Effects of drug treatment on integrin related signaling, Akt and p70S6kinase activation, histone H3 and H4 acetylation were also determined. Separate application of RAD001 or VPA distinctly reduced tumor cell adhesion, migration and invasion, accompanied by elevated Akt activation and p70S6kinase de-activation. Integrin subtype expression was altered significantly by both compounds (VPA > RAD001). When both drugs were used in concert additive effects were observed on the migratory and invasive behavior but not on tumor-endothelium and tumor-matrix interaction. Separate mTOR or HDAC inhibition slows processes related to tumor metastasis. The RAD001-VPA combination showed advantage over VPA monotreatment with particular respect to migration and invasion. Ongoing studies are required to assess the relevance of VPA monotherapy versus VPA-RAD001 combination on tumor cell motility.

Keywords

RAD001 Valproic acid Prostate carcinoma Invasion Adhesion 

Abbreviations

HDAC

Histone deacetylase

VPA

Valproic acid

mTOR

Mammalian target of rapamycin

HUVEC

Human endothelial cells

ILK

Integrin-linked kinase

FAK

Focal adhesion kinase

Notes

Acknowledgements

We would like to thank Karen Nelson for critically reading the manuscript. This work was supported by the “Jung-Stiftung”.

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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Steffen Wedel
    • 1
  • Lukasz Hudak
    • 1
  • Jens-Michael Seibel
    • 1
  • Jasmina Makarević
    • 1
  • Eva Juengel
    • 1
  • Igor Tsaur
    • 1
  • Christoph Wiesner
    • 1
  • Axel Haferkamp
    • 1
  • Roman A. Blaheta
    • 1
  1. 1.Department of UrologyJohann Wolfgang Goethe-UniversityFrankfurt am MainGermany

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