Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer

J. Carretero, P. P. Medina, R. Blanco, L. Smit, M. Tang, G. Roncador, L. Maestre, E. Conde, F. Lopez-Rios, H. C. Clevers, M. Sanchez-Cespedes

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

122 Citaten (Scopus)

Samenvatting

LKB1, mutated in Peutz-Jeghers and in sporadic lung tumours, phosphorylates a group of protein kinases named AMP-activated protein kinase (AMPK)-related kinases. Among them is included the AMPK, a sensor of cellular energy status. To investigate the relevance of LKB1 in lung carcinogenesis, we study several lung cancer cells with and without LKB1-inactivating mutations. We report that LKB1-mutant cells are deficient for AMPK activity and refractory to mTOR inhibition upon glucose depletion but not growth-factor deprivation. The requirement for wild-type LKB1 to properly activate AMPK is further demonstrated in genetically modified cancer cells. In addition, LKB1-deficient lung primary tumours had diminished AMPK activity, assessed by complete absence or low level of phosphorylation of its critical substrate, acetyl-CoA carboxylase. We also demonstrate that LKB1 wild-type cells are more resistant to cell death upon glucose withdrawal than their mutant counterparts. Finally, modulation of AMPK activity did not affect PI3K/AKT signalling, an advantage for the potential use of AMPK as a target for cancer therapy in LKB1 wild-type tumours. Thus, sustained abrogation of cell energetic checkpoint control, through alterations at key genes, appear to be an obligatory step in the development of some lung tumours.

Originele taal-2Engels
Pagina's (van-tot)1616-1625
Aantal pagina's10
TijdschriftOncogene
Volume26
Nummer van het tijdschrift11
DOI's
StatusGepubliceerd - 8 mrt. 2007
Extern gepubliceerdJa

Vingerafdruk

Duik in de onderzoeksthema's van 'Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer'. Samen vormen ze een unieke vingerafdruk.

Citeer dit