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.