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

Regan M. Memmott, Joell Gills, Melinda Hollingshead, Margaret C. Powers, Zhiping Chen, Bruce Kemp, Alan Kozikowski, Phillip A. Dennis

Research output: Contribution to journalArticle

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, CaMKKβ, 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 CaMKKβ, suggesting that CaMKKβ contributes to PIA-induced AMPK activation in cells. AMPK activation promoted PIA-induced cytotoxicity because PIAs were less cytotoxic in AMPKα-/- murine embryonic fibroblasts or LKB1-mutant NSCLC cells transfected with mutant AMPK. This mechanism was also relevant in vivo. Treatment of LKB1-mutant NSCLC xenografts with PIA decreased tumor volume by ∼50% and activated AMPK. These studies show that PIAs recapitulate the activity of two tumor suppressors (PTEN and LKB1) that converge on mTOR. Moreover, they suggest that PIAs might have utility in the treatment of LKB1-mutant lung adenocarcinomas.

Original languageEnglish (US)
Pages (from-to)580-588
Number of pages9
JournalCancer Research
Volume68
Issue number2
DOIs
StatePublished - Jan 15 2008
Externally publishedYes

Fingerprint

AMP-Activated Protein Kinases
Phosphatidylinositols
Non-Small Cell Lung Carcinoma
Ether
Lipids
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non-small cell lung cancer cells. / Memmott, Regan M.; Gills, Joell; Hollingshead, Melinda; Powers, Margaret C.; Chen, Zhiping; Kemp, Bruce; Kozikowski, Alan; Dennis, Phillip A.

In: Cancer Research, Vol. 68, No. 2, 15.01.2008, p. 580-588.

Research output: Contribution to journalArticle

Memmott, Regan M. ; Gills, Joell ; Hollingshead, Melinda ; Powers, Margaret C. ; Chen, Zhiping ; Kemp, Bruce ; Kozikowski, Alan ; Dennis, Phillip A. / Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non-small cell lung cancer cells. In: Cancer Research. 2008 ; Vol. 68, No. 2. pp. 580-588.
@article{30c071b1ce044f26b73e36ba3f009a6d,
title = "Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non-small cell lung cancer cells",
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, CaMKKβ, 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 CaMKKβ, suggesting that CaMKKβ contributes to PIA-induced AMPK activation in cells. AMPK activation promoted PIA-induced cytotoxicity because PIAs were less cytotoxic in AMPKα-/- murine embryonic fibroblasts or LKB1-mutant NSCLC cells transfected with mutant AMPK. This mechanism was also relevant in vivo. Treatment of LKB1-mutant NSCLC xenografts with PIA decreased tumor volume by ∼50{\%} and activated AMPK. These studies show that PIAs recapitulate the activity of two tumor suppressors (PTEN and LKB1) that converge on mTOR. Moreover, they suggest that PIAs might have utility in the treatment of LKB1-mutant lung adenocarcinomas.",
author = "Memmott, {Regan M.} and Joell Gills and Melinda Hollingshead and Powers, {Margaret C.} and Zhiping Chen and Bruce Kemp and Alan Kozikowski and Dennis, {Phillip A.}",
year = "2008",
month = "1",
day = "15",
doi = "10.1158/0008-5472.CAN-07-3091",
language = "English (US)",
volume = "68",
pages = "580--588",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non-small cell lung cancer cells

AU - Memmott, Regan M.

AU - Gills, Joell

AU - Hollingshead, Melinda

AU - Powers, Margaret C.

AU - Chen, Zhiping

AU - Kemp, Bruce

AU - Kozikowski, Alan

AU - Dennis, Phillip A.

PY - 2008/1/15

Y1 - 2008/1/15

N2 - 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, CaMKKβ, 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 CaMKKβ, suggesting that CaMKKβ contributes to PIA-induced AMPK activation in cells. AMPK activation promoted PIA-induced cytotoxicity because PIAs were less cytotoxic in AMPKα-/- murine embryonic fibroblasts or LKB1-mutant NSCLC cells transfected with mutant AMPK. This mechanism was also relevant in vivo. Treatment of LKB1-mutant NSCLC xenografts with PIA decreased tumor volume by ∼50% and activated AMPK. These studies show that PIAs recapitulate the activity of two tumor suppressors (PTEN and LKB1) that converge on mTOR. Moreover, they suggest that PIAs might have utility in the treatment of LKB1-mutant lung adenocarcinomas.

AB - 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, CaMKKβ, 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 CaMKKβ, suggesting that CaMKKβ contributes to PIA-induced AMPK activation in cells. AMPK activation promoted PIA-induced cytotoxicity because PIAs were less cytotoxic in AMPKα-/- murine embryonic fibroblasts or LKB1-mutant NSCLC cells transfected with mutant AMPK. This mechanism was also relevant in vivo. Treatment of LKB1-mutant NSCLC xenografts with PIA decreased tumor volume by ∼50% and activated AMPK. These studies show that PIAs recapitulate the activity of two tumor suppressors (PTEN and LKB1) that converge on mTOR. Moreover, they suggest that PIAs might have utility in the treatment of LKB1-mutant lung adenocarcinomas.

UR - http://www.scopus.com/inward/record.url?scp=39049157916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39049157916&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-07-3091

DO - 10.1158/0008-5472.CAN-07-3091

M3 - Article

C2 - 18199555

AN - SCOPUS:39049157916

VL - 68

SP - 580

EP - 588

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 2

ER -