Metastasis and AKT activation

Abstract

Metastasis is responsible for 90% of cancer patient deaths. More information is needed about the molecular basis for its potential detection and treatment. The activated AKT kinase is necessary for many events of the metastatic pathway including escape of cells from the tumor's environment, into and then out of the circulation, activation of proliferation, blockage of apoptosis, and activation of angiogenesis. A series of steps leading to metastatic properties can be initiated upon activation of AKT by phosphorylation on Ser-473. These findings lead to the question of how this activation is connected to metastasis. Activated AKT phosphorylates GSK-3beta causing its proteolytic removal. This increases stability of the negative transcription factor SNAIL, thereby decreasing transcription of the transmembrane protein E-cadherin that forms adhesions between adjacent cells, thereby permitting their detachment. How is AKT hyperactivated in metastatic cells? Increased PI3K or TORC2 kinase activity- or decreased PHLPP phosphatase could be responsible. Furthermore, a positive feedback mechanism is that the decrease of E-cadherin lowers PTEN and thereby increases PIP3, further activating AKT and metastasis.

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

“…However, our results do not favor the latter mechanism, as PD98059 (and UO126) only potentiates ligand-induced Akt activation and cell motility, but not the basal, in our experimental settings ( Figure 5 and Supplementary Figure 4). Nevertheless, our findings and several other studies (Schlessinger and Hall, 2004;Zhou et al, 2004;Qiao et al, 2008;Wu et al, 2009;Yang and Wolf, 2009) highlight that Akt is a critical modulator, when activated by receptor tyrosine kinases (including the EGFR family), in cancer invasion and metastasis, which frequently involves transcriptional repression of E-cadherin by Snail, the key step during EMT.…”

“…It is widely believed that downregulation of E-cadherin occurs through transcriptional repression mediated by the protein, Snail (Cano et al, 2000;Peinado et al, 2007;Moreno-Bueno et al, 2008). Accumulating evidence indicates that the EGFR family and its downstream signaling pathways (for example, PI3K-Akt and rat sarcoma-MEK-ERK) regulate the expression of Snail (Lee et al, 2008;Qiao et al, 2008;Hipp et al, 2010), suggesting that pharmacological inhibition of these pathways may prevent the loss of E-cadherin function and thereby acquisition of invasive motility.…”

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

“…Indeed, Akt stimulates cell survival and proliferation by acting on a number of proteins (Forkhead, IKK, Mdm2, TSC1/2) that are apparently not affected by ASAH1. [9][10][11] Furthermore, Akt was shown to promote invasiveness by upregulating the expression of IGF-1 receptor, β1-integrin and MMP-9, respectively, 20,33,34 whereas ASAH1 was shown to promote proliferation and survival by affecting retinoblastoma protein (RB) phosphorylation 41 and Bax levels, 42 and to stimulate invasion by upregulating cathepsin B. 32 In addition, there may be crosstalk between ASAH1 and Akt-regulated pathways.…”

“…[9][10][11] PI3K-catalyzed formation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), is required for Akt recruitment to the plasma membrane and subsequent activating phosphorylation at T308 and S473. Akt phosphorylates many substrates that mediate tumor progression.…”

VIP and PACAP analogs regulate therapeutic targets in high-risk neuroblastoma cells

“…We next wondered whether VIP acts on AKT activity. Phosphorylation of AKT at serine 473 is necessary for its kinase activity [39]. The data indicated that VIP decreased phosphorylation at serine 473 (P-AKT) after 3 and 6 h of treatment with VIP, in correlation with reduced MYCN expression.…”