Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 1, pp 79–86

Kinase activation profile associated with TGF-β-dependent migration of HCC cells: a preclinical study

  • Emilia Fransvea
  • Antonio Mazzocca
  • Angela Santamato
  • Amalia Azzariti
  • Salvatore Antonaci
  • Gianluigi Giannelli
Original Article

DOI: 10.1007/s00280-010-1459-x

Cite this article as:
Fransvea, E., Mazzocca, A., Santamato, A. et al. Cancer Chemother Pharmacol (2011) 68: 79. doi:10.1007/s00280-010-1459-x

Abstract

Purpose

To identify the molecular mechanisms responsible for tumor cell migration is essential for developing agents that can prevent the relapse or the metastatic spread of hepatocellular carcinoma (HCC).

Methods

In this study, we investigated the effects of the transforming growth factor-β receptor I inhibitor LY2109761 on two different human HCC cell lines, in vitro and in vivo.

Results

LY2109761 inhibits HCC migration in a dose-dependent manner. This inhibition is associated with the decreased phosphorylation of SMAD-2, FAK and β1-integrin, and with increased levels of E-cadherin. By contrast, LY2109761 did not alter the phosphorylation pattern of p38MAPkinase. In a two- and a three-day time-course and in dose-titration experiments, LY2109761 inhibited HCC migration as well as phospho-SMAD-2 and the adhesion proteins. LY2109761 showed the best effect on day 2 at 1 nM and for 3 days at 100 nM concentration. This suggests that maximum effects were sustained for several days and were not dependent on excess concentrations. Finally, in a xenograft model of HCC, LY2109761 strongly inhibits tumor growth, intravasation and metastasis at the aforementioned lower concentrations.

Conclusions

In conclusion, inhibition of transforming growth factor-β (TGF-β) appears to occur at low concentrations of LY2109761 that displays multiple effects on kinases that control HCC cell migration. These findings may help the design of future clinical trials with inhibitors of TGF-β.

Keywords

Hepatocellular carcinomaE-cadherinSmad-2Tissue microenvironmentTherapies

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Emilia Fransvea
    • 1
  • Antonio Mazzocca
    • 1
  • Angela Santamato
    • 1
  • Amalia Azzariti
    • 2
  • Salvatore Antonaci
    • 1
  • Gianluigi Giannelli
    • 1
    • 3
  1. 1.Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal MedicineUniversity of Bari Medical SchoolBariItaly
  2. 2.Clinical Experimental Oncology LaboratoryNational Cancer Institute BariBariItaly
  3. 3.Dipartimento di Clinica Medica, Immunologia e Malattie InfettiveSezione di Medicina Interna, PoliclinicoBariItaly