The Sir Hans Krebs Lecture. How a lipid mediates tumour suppression. Delivered on 29 June 2010 at the 35th FEBS Congress in Gothenburg, Sweden.
Phosphorylated derivatives of the membrane lipid phosphatidylinositol (PtdIns), known as phosphoinositides (PIs), regulate membrane-proximal cellular processes by recruiting specific protein effectors involved in cell signalling, membrane trafficking and cytoskeletal dynamics. Two PIs that are generated through the activities of distinct PI 3-kinases (PI3Ks) are of special interest in cancer research. PtdIns(3,4,5)P₃, generated by class I PI3Ks, functions as tumour promotor by recruiting effectors involved in cell survival, proliferation, growth and motility. Conversely, there is evidence that PtdIns3P, generated by class III PI3K, functions in tumour suppression. Three subunits of the class III PI3K complex (Beclin 1, UVRAG and BIF-1) have been independently identified as tumour suppressors in mice and humans, and their mechanism of action in this context has been proposed to entail activation of autophagy, a catabolic pathway that is considered to mediate tumour suppression by scavenging damaged organelles that would otherwise cause DNA instability through the production of reactive oxygen species. Recent studies have revealed two additional functions of PtdIns3P that might contribute to its tumour suppressor activity. The first involves endosomal sorting and lysosomal downregulation of mitogenic receptors. The second involves regulation of cytokinesis, which is the final stage of cell division. Further elucidation of the mechanisms of tumour suppression mediated by class III PI3K and PtdIns3P will identify novel Achilles' heels of the cell's defence against tumourigenesis and will be useful in the search for prognostic and diagnostic biomarkers in cancer.
Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway. stenmark@ulrik.uio.no
Harald
H
Stenmark
D000818:Animals; D001343:Autophagy; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D048749:Cytokinesis; D004249:DNA Damage; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D025521:Tumor Suppressor Proteins; C055525:phosphatidylinositol 3-phosphate; D058546:Class III Phosphatidylinositol 3-Kinases