Lovastatin disrupts early events in insulin signaling: a potential mechanism of lovastatin's anti-mitogenic activity

Biochemical and Biophysical Research Communications
T F McGuireS M Sebti

Abstract

The mechanism by which lovastatin lowers cholesterol levels is well characterized but little is known about its anti-mitogenic and anti-tumorigenic mechanism. Here we demonstrate that lovastatin disrupts early events in the mitogenic signaling pathways of insulin. Insulin treatment (200 mM) of quiescent HIR rat-1 fibroblasts results in an 8-fold stimulation of phosphatidylinositol-3-kinase (PI-3-K) activity. Overnight pretreatment of cells with lovastatin (20 microM) inhibits insulin stimulation of PI-3-K activity by 75%. Immunoprecipitation and immunoblotting experiments using antibodies against the regulatory subunit of PI-3-K (p85), phosphotyrosine, and insulin receptor alpha and beta subunits demonstrate that lovastatin inhibits the association of p85 with tyrosine phosphorylated insulin receptor substrate-1 and the beta subunit of the insulin receptor. Furthermore, lovastatin dramatically reduces (70-100%) the level of tyrosine phosphorylated insulin receptor beta subunit following insulin stimulation. These results clearly demonstrate that lovastatin disrupts early events of insulin mitogenic signaling by reducing the levels of tyrosine phosphorylated beta subunit and suggest that this disruption is a potential mechanism ...Continue Reading

Citations

Jan 5, 1999·American Journal of Respiratory and Critical Care Medicine·A TanP B Bitterman
Dec 4, 2003·Biological & Pharmaceutical Bulletin·Makoto KandaKazuo Ichihara
Oct 6, 2015·Expert Opinion on Drug Safety·Aris P AgouridisMoses S Elisaf
Jun 15, 2007·Alcoholism, Clinical and Experimental Research·Martin J J RonisJan Calissendorff
Nov 16, 2014·Current Atherosclerosis Reports·Dick C ChanGerald F Watts
May 13, 2008·Journal of Pharmacological Sciences·Akira TakaguriKazuo Ichihara
Apr 19, 2017·Nutrition, Metabolism, and Cardiovascular Diseases : NMCD·M CasulaA L Catapano
Dec 13, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Eman AwadHelga Stopper
May 1, 2013·Expert Review of Endocrinology & Metabolism·Maciej Banach, Dimitri P Mikhailidis
Jan 1, 2005·Toxicology Mechanisms and Methods·Jerzy Beltowski
Sep 19, 2019·Journal of Atherosclerosis and Thrombosis·Yongin ChoEun Seok Kang
Apr 18, 2017·F1000Research·Daniel P GilT M Murali
Nov 20, 2004·American Journal of Physiology. Heart and Circulatory Physiology·Hiroaki NishimatsuYasunobu Hirata

❮ Previous
Next ❯

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.