Mechanism implicated in the EGF-stimulated ErbB2 levels in absence of PI3K/Akt pathway in LNCaP cells

M. ALICIA CORTÉS; A. PEDROSA-AMADO; JAVIER RODRIGUEZ-UBREVA; ARIEL E. CARIAGA-MARTINEZ; PILAR LÓPEZ-RUIZ; BEGOÑA COLÁS

Vienna

Congreso; 32nd FEBS Molecular Machines; 2007

FEBS

The PI3K/Akt pathway is constitutively active in LNCaP human prostate cancer cells due to a mutation in the PTEN. The PI3K/ AKT is important for cell survival owing to treatment with the PI3K inhibitor LY-294002, in the absence of androgens, leads to apoptosis. This apoptotic effect can be antagonized by EGF. In this context, we found that EGF, in the presence of LY, increased the mRNA and the membrane protein levels of ErbB2. Since ErbB2 has been related with a more aggressive phenotype in pros- tate cancer, the aim of the present study was to study the mecha- nisms implicated in the ErbB2 up-regulation, analyzing modifications of ErbB2 synthesis and degradation. We saw that ErbB2 specifically interacts with Hsp90, a chaperone implicated in the stabilization of ErbB2. This interaction was enhanced when the LNCaP cells were incubated with EGF in the presence of LY. Dis- ruption of Hsp90 function by geldanamycin prevented the EGF- induced ErbB2 up-regulation in the presence of LY. We also study the effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor that regulates gene expression. Treatment with SAHA abrogated the increase of ErbB2 mRNA and protein levels induced by EGF in the presence of LY. Our results indicate that the treatment with EGF and LY up-regulate ErbB2 via different mechanisms.