title: Polyamine production is downstream and upstream of oncogenic PI3K signalling and contributes to tumour cell growth.
abstract: PI3K (phosphoinositide 3-kinase) signalling pathways regulate a large array of cell biological functions in normal and cancer cells. In the present study we investigated the involvement of PI3K in modulating small molecule metabolism. A LC (liquid chromatography)-MS screen in colorectal cancer cell lines isogenic for oncogenic PIK3CA mutations revealed an association between PI3K activation and the levels of polyamine pathway metabolites, including 5-methylthioadenosine, putrescine and spermidine. Pharmacological inhibition confirmed that the PI3K pathway controls polyamine production. Despite inducing a decrease in PKB (protein kinase B)/Akt phosphorylation, spermidine promoted cell survival and opposed the anti-proliferative effects of PI3K inhibitors. Conversely, polyamine depletion by an ornithine decarboxylase inhibitor enhanced PKB/Akt phosphorylation, but suppressed cell survival. These results suggest that spermidine mediates cell proliferation and survival downstream of PI3K/Akt and indicate that these two biochemical pathways control each other's activities, highlighting a mechanism by which small molecule metabolism feeds back to regulate kinase signalling. Consistent with this feedback loop having a functional role in these cell models, pharmacological inhibitors of PI3K and ornithine decarboxylase potentiated each other in inhibiting tumour growth in a xenograft model. The results of the present study support the notion that the modulation of spermidine concentrations may be a previously unrecognized mechanism by which PI3K sustains chronic proliferation of cancer cells.
authors: Analytical Signaling Group, Centre for Cell Signaling, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors: Vinothini
authors: V
authors: Rajeeve
authors: Wayne
authors: W
authors: Pearce
authors: Marta
authors: M
authors: Cascante
authors: Bart
authors: B
authors: Vanhaesebroeck
authors: Pedro R
authors: PR
authors: Cutillas
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D013058:Mass Spectrometry; D055442:Metabolome; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D011073:Polyamines / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D011073:Polyamines; D019869:Phosphatidylinositol 3-Kinases