Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non small cell lung cancer cells

Cancer Research
Regan M MemmottPhillip A Dennis

Abstract

Loss of function of the tumor suppressor LKB1 occurs in 30% to 50% of lung adenocarcinomas. Because LKB1 activates AMP-activated protein kinase (AMPK), which can negatively regulate mTOR, AMPK activation might be desirable for cancer therapy. However, no known compounds activate AMPK independently of LKB1 in vivo, and the usefulness of activating AMPK in LKB1-mutant cancers is unknown. Here, we show that lipid-based Akt inhibitors, phosphatidylinositol ether lipid analogues (PIA), activate AMPK independently of LKB1. PIAs activated AMPK in LKB1-mutant non-small cell lung cancer (NSCLC) cell lines with similar concentration dependence as that required to inhibit Akt. However, AMPK activation was independent of Akt inhibition. AMPK activation was a major mechanism of mTOR inhibition. To assess whether another kinase capable of activating AMPK, CaMKK beta, contributed to PIA-induced AMPK activation, we used an inhibitor of CaMKK, STO-609. STO-609 inhibited PIA-induced AMPK activation in LKB1-mutant NSCLC cells, and delayed AMPK activation in wild-type LKB1 NSCLC cells. In addition, AMPK activation was not observed in NSCLC cells with mutant CaMKK beta, suggesting that CaMKK beta contributes to PIA-induced AMPK activation in cells....Continue Reading

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Citations

Jul 25, 2009·Nature Reviews. Cancer·David B Shackelford, Reuben J Shaw
Nov 26, 2008·Oncogene·A F Hezel, N Bardeesy
Sep 3, 2010·Cancer Prevention Research·Regan M MemmottPhillip A Dennis
Sep 18, 2012·BMC Cancer·Peter J MazzoneMadhu Sasidhar
Dec 3, 2009·Haematologica·Sophie ParkDidier Bouscary
Apr 26, 2011·Familial Cancer·Montse Sanchez-Cespedes
May 27, 2014·Expert Review of Clinical Pharmacology·Flavia Franconi, Ilaria Campesi
Oct 8, 2008·The Journal of Cell Biology·Michael DegtyarevKui Lin
Aug 15, 2009·Expert Opinion on Investigational Drugs·Alberto M MartelliJames A McCubrey
Nov 26, 2010·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Adam I Marcus, Wei Zhou
Oct 2, 2015·The FEBS Journal·Tiziana MonteverdeDaniel J Murphy
May 13, 2010·Biochemical and Biophysical Research Communications·Seung-Lark HwangYoung-Chae Chang
Sep 29, 2011·Mechanisms of Ageing and Development·Artur Zajkowicz, Marek Rusin
Sep 3, 2013·Asian Pacific Journal of Cancer Prevention : APJCP·Dong HanMan-Xiang Li
Mar 27, 2015·Oncotarget·Weidong LiBaojin Hua
Apr 2, 2009·Cancer Prevention Research·Judith R FayJames A Crowell
May 24, 2012·Journal of Cell Science·Simone CardaciMaria Rosa Ciriolo

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