Background: Aspirin, the pro-drug of salicylate, is associated with reduced incidence of death from cancers and is commonly prescribed in combination with metformin in individuals with type 2 diabetes. Salicylate activates the AMP-activated protein kinase (AMPK) via Ser108 of the AMPK β1 subunit, a mechanism that is distinct from metformin, which increases AMP:ATP. Many cancers have high rates of fatty acid synthesis and AMPK inhibits this pathway through phosphorylation of acetyl-CoA carboxylase (ACC). It is unknown if targeting the AMPK-ACC-lipogenic pathway using salicylate and metformin may be effective for inhibiting cancer cell survival.
Results: Salicylate suppresses clonogenic survival of prostate and lung cancer cells at therapeutic concentrations of aspirin. These clinically achievable concentrations of salicylate activated AMPK per the increasing phosphorylation of ACC and suppressing the activity of mTOR effectors kinase p70-S6 kinase and S6; effects that were enhanced with the addition of metformin and blunted in mouse embryonic fibroblasts (MEFS) deficient in AMPK β1. MEF cells deficient in AMPK β1 were more resistant to salicylates inhibitory effect on proliferation. Supplementation of media with fatty acids and mevalonate reverses the suppressive effects on cell survival indicating the inhibition of de novo lipogenesis is likely important.
Conclusions: Salicylate increases ACC phosphorylation, reduces phosphorylation of mTOR targets and inhibits de novo lipogenesis in prostate and lung cancer cells, with concentrations of salicylate achievable through the ingestion of Aspirin (0.25-1.0mM) these effects are blunted in AMPK β1 deficient cells. Effects on AMPK activity via ACC phosphorylation as well as reductions in mTOR signalling targets and de novo lipogenesis are enhanced when used in combination with metformin. Suppressive effects on prostate and lung cancer cell survival are ameliorated when media is supplemented with mevalonate and fatty acids. Pre-clinical studies evaluating the use of salicylates alone and with metformin to inhibit de novo lipogenesis and the growth of prostate and lung cancers are warranted. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/16883 |
| Date | 06 1900 |
| Creators | O'Brien, Andrew |
| Contributors | Steinberg, Gregory R., Tsakiridis, Theodoros, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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