Role in Cancer Akt/PKB signaling pathway

pi3k-akt pathway proteins involved in cancer. oncogenes (activation increases in cancer) green , tumour suppressors (inactivated or lost in cancer) red.

aberrant activation of akt, either via pi3k or independently of pi3k, associated malignancy. studies have identified gene amplification of akt isoforms in many types of cancer, including glioblastoma, ovarian, pancreatic , breast cancers. akt up-regulated in terms of mrna production in breast , prostate cancer. functional inactivation of pten, major pi3k antagonist, can occur in cancer cells point mutation, gene deletion or epigenetic mechanisms. mutation in pathway can affect receptor tyrosine kinases, growth factors, ras , pi3k p110 subunit, leading abnormal signalling activity. therefore, many of proteins in pathway targets cancer therapeutics. in addition effects on cell survival , cell cycle progression, pi3k-akt pathway promotes other characteristics of cancer cells. hyperactivity of pathway promotes epithelial-mesenchymal transition (emt) , metastasis due effects on cell migration.

angiogenesis

angiogenesis, formation of new blood vessels, critical tumour cells survive , grow in nutrient-depleted conditions. akt activated downstream of vascular endothelial growth factor (vegf) in endothelial cells in lining of blood vessels, promoting survival , growth. akt contributes angiogenesis activating endothelial nitric oxide synthase (enos), increases production of nitric oxide (no). stimulates vasodilation , vascular remodelling. signalling through pi3k-akt pathway increases translation of hypoxia-inducible factor α (hif1α , hif2α) transcription factors via mtor. hif promotes gene expression of vegf , glycolytic enzymes, allowing metabolism in oxygen-depleted environments.

glucose metabolism

in cancer cells, increase in akt signalling correlates increase in glucose metabolism, compared normal cells. cancer cells favour glycolysis energy production on mitochondrial oxidative phosphorylation, when oxygen supply not limited. known warburg effect, or aerobic glycolysis.

akt affects glucose metabolism increasing translocation of glucose transporters glut1 , glut4 plasma membrane, increasing hexokinase expression , phosphorylating gsk3 stimulates glycogen synthesis. activates glycolysis enzymes indirectly, via hif transcription factors , phosphorylation of phosphofructokinase-2 (pfk2) activates phosphofructokinase-1 (pfk1).