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

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.

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Acknowledgements

We thank our collaborators in the Tumour Bank Network. We also acknowledge the technical help of the Confocal Microscopy and Flow Cytometry, Immunohistochemistry and Protein Technology Units of the CNIO. The work was supported by the Spanish Ministerio de EducaciĂłn (SAF2005-00626). M Sanchez-Cespedes is supported by the Ramon y Cajal Programme and PP Medina by the Comunidad Autonoma de Madrid; R Blanco is supported by the Fondo de Investigaciones Sanitarias (FIS).

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Correspondence to M Sanchez-Cespedes.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Carretero, J., Medina, P., Blanco, R. et al. Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer. Oncogene 26, 1616–1625 (2007). https://doi.org/10.1038/sj.onc.1209951

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