Akt kinase is known to play a central role in many cellular processes including proliferation, differentiation, migration (adhesion) and apoptosis. Survival signals induced by several receptors are mediated mainly by Phosphatidylinositol-3-kinase (PI3K) / Akt kinase. Constitutive activation of Akt kinase is frequently described in many types of human cancers. Relatively less recognized are mechanisms that involve Akt kinase in signal transduction mediated through adhesion molecules including cell-cell and cell-extra cellular matrix proteins interactions.

We were able to show that two adhesion molecules – alpha3beta1 integrin and N-cadherin are likely involved in signal transduction that recruits Akt kinase. Laminin-5 (LN-5) – integrin dependent signaling pathway activates matrix metalloproteinase (MMPs) in human melanoma cells. Increased level of phospho–AKT (pAkt, Ser-473) in the cells cultured on LN-5 was observed. This signaling pathway, necessary for migration of melanoma cells, was shown to involve PI3-K/Akt activity as the addition of the PI3-K specific inhibitor, LY294002, decreased the level of pAkt (Ser-473) and in parallel the expression and activity of MMP-2 and 9 in melanoma cells.

Independent study on the role of N-cadherin - which upon cancer progression replaces E-cadherin in number of cells - showed that silencing of its expression by siRNA in melanoma cells reduced phosphorylation of Akt (Ser 473) and in parallel significantly decreased cell proliferation (50-70%). N-cadherin is known to promote in vitro migration and is likely involved in inhibition of apoptosis in melanoma cells. We have proven that blocking of the PI3K/Akt pathway with LY294002 and PI3K/Akt––N-cadherin–beta-catenin–actin interactions with cytochalasine D significantly increases caspase-3 activity in human melanoma cells.

We recently postulated that beta-catenin plays important role in sustaining survival signals in prostate cancer cells. The increased expression of E-cadherin and/or decreased expression of N-cadherin was accompanied by reduced expression of beta-catenin and decreased proliferation of prostate cancer cells and the effect likely depended on their androgen sensitivity (1). Our most recent results indicate that Akt promotes androgen-independent survival of prostate cancer cells by modulating the expression and activation of the androgen receptor (AR). This pathway seems to involve beta-catenin, too.

Therefore, we try to look for the possible interaction (cross-talk) between Akt kinase and beta-catenin signaling pathways which might be crucial for development and progression of cancer.

(1) Laidler P., Dulińska J., Mrozicki S. (2007) Arch. Biochem. Biophys., in press

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1. Role of androgen receptor in prostate cancer cells progression