The PTEN/PI3K/AKT Signalling Pathway in Cancer, Therapeutic Implications

Abstract

PTEN/PI3K/AKT constitutes an important pathway regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation and cell growth. PTEN is a dual protein/lipid phosphatase which main substrate is the phosphatidyl-inositol,3,4,5 triphosphate (PIP3), the product of PI3K. Increase in PIP3 recruits AKT to the membrane where it is activated by other kinases also dependent on PIP3. Many components of this pathway have been described as causal forces in cancer. PTEN activity is lost by mutations, deletions or promoter methylation silencing at high frequency in many primary and metastatic human cancers. Germ line mutations of PTEN are found in several familial cancer predisposition syndromes. Activating mutations which have been reported for PI3K and AKT, in tumours are able to confer tumourigenic properties in several cellular systems. Additionally, the binding of PI3K to oncogenic ras is essential for the transforming properties of ras. In summary, the data strongly support the view of the PTEN/PI3K/AKT pathway as an important target for drug discovery.

Human Umbilical Cord Blood Cells Protect Oligodendrocytes from Brain Ischemia through Akt Signal Transduction

“…Their actions have not only been implicated in neurodegenerative diseases but also as a target for cancer treatment and immune functioning (37)(38)(39)(40). Administration of peroxiredoxin 3 protected neurons from ischemic insult resulting in enhanced behavioral recovery (41).…”

cAMP/CREB-mediated Transcriptional Regulation of Ectonucleoside Triphosphate Diphosphohydrolase 1 (CD39) Expression

“…The PI3K subunit p85␣ (serine 83) is phosphorylated in vivo and in vitro by PKA (27). PI3K catalyzes the production of the lipid secondary messenger phosphatidylinositol 3,4,5-triphosphate, which in turn activates a wide range of its own downstream targets, including the serine/threonine kinase Akt (36). The PI3K-Akt pathway regulates multiple cellular processes, including cell proliferation, survival, growth, and motility (35).…”

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…Constitutive pathway activation can result from the distinct and/or complementary biological events including (i) constitutively active mutants or amplification of receptor tyrosine kinases (for example, epidermal growth factor receptor or ErbB2) leading to constitutive recruitment and activation of PI3K and downstream effectors; (ii) amplification of PI3K; (iii) presence of activating mutations in the PIK3CA gene encoding the p110a catalytic subunit; (iv) overexpression of the downstream kinase Akt; (v) loss or inactivating mutations of the tumor suppressor gene PTEN, an endogenous negative regulator of the PI3K pathway or (vi) constitutive recruitment and activation by mutant forms of the Ras oncogene (Carnero et al, 2008;Tokunaga et al, 2008;Maira et al, 2008b). The preceding alterations trigger a cascade of biological events, from cell growth and proliferation to survival and migration, which drive tumor progression.…”