1. ¹Lung Cancer Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
2. ²Hubrecht Laboratory, Center for Biomedical Genetics, Utrecht, The Netherlands
3. ³Monoclonal Antibodies Unit, (CNIO), Hospital Universitario 12 de Octubre, Madrid, Spain
4. ⁴Pathology Department, Hospital Universitario 12 de Octubre, Madrid, Spain

Correspondence: Dr M Sanchez-Cespedes, Lung Cancer Group, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain. E-mail: msanchez@cnio.es

Received 19 June 2006; Revised 21 July 2006; Accepted 21 July 2006; Published online 4 September 2006.

Abstract

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.