STAT3 regulates PDK1 expression and Akt activity in melanoma.

MARIA ELISA PICCO, MARIA SOL BRAVO, DAIANA MARTIRE-GRECO, NATALIA FERNANDEZ, HYUNGSOO KIM, ZEEV RONAI, PABLO LOPEZ-BERGAMI.

Congreso; Society for Melanoma Research 2009 International Congress.; 2009

The failure of targeted therapies attempted in melanoma indicates that a more profound understanding of its altered signaling pathways and particularly the interplay among them, is required. The PI3K/Akt and the JAK/STAT3 pathways are activated in melanoma and are usually depicted as parallel paths to oncogenesis. The evidence showing a link between them is scarce or controversial. In the present work we studied the regulation of the expression of Phosphoinositide-Dependent Kinase-1 (PDK1), a master kinase involved in Akt phosphorylation and activation, by STAT3. Expression of dominant negative STAT3 constructs STAT3b and STAT3Y as well as siRNA against STAT3 inhibited both PDK1 mRNA and protein levels. Serial deletions of the 5’ region of the PDK1 promoter allowed to map two functional STAT3 responsive elements at -265 and -130 of the PDK1 promoter. STAT3-dependent transcription of PDK1 was abolished by mutations that simultaneously destroy both elements. The reduction on PDK1 expression following STAT3 inhibition resulted in an weakened Akt phosphorylation and activity. These results indicate that constitutive activation of STAT3 contributes to Akt activity through upregulation of PDK1 expression.