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A novel LKB1 isoform enhances AMPK metabolic activity and displays oncogenic properties

Oncogene volume 34, pages 2337–2346 (2015)Cite this article

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Abstract

The LKB1 tumor suppressor gene encodes a master kinase that coordinates the regulation of energetic metabolism and cell polarity. We now report the identification of a novel isoform of LKB1 (named ΔN-LKB1) that is generated through alternative transcription and internal initiation of translation of the LKB1 mRNA. The ΔN-LKB1 protein lacks the N-terminal region and a portion of the kinase domain. Although ΔN-LKB1 is catalytically inactive, it potentiates the stimulating effect of LKB1 on the AMP-activated protein kinase (AMPK) metabolic sensor through a direct interaction with the regulatory autoinhibitory domain of AMPK. In contrast, ΔN-LKB1 negatively interferes with the LKB1 polarizing activity. Finally, combining in vitro and in vivo approaches, we showed that ΔN-LKB1 has an intrinsic oncogenic property. ΔN-LKB1 is expressed solely in the lung cancer cell line, NCI-H460. Silencing of ΔN-LKB1 decreased the survival of NCI-H460 cells and inhibited their tumorigenicity when engrafted in nude mice. In conclusion, we have identified a novel LKB1 isoform that enhances the LKB1-controlled AMPK metabolic activity but inhibits LKB1-induced polarizing activity. Both the LKB1 tumor suppressor gene and the oncogene ΔN-LKB1 are expressed from the same locus and this may account for some of the paradoxical effects of LKB1 during tumorigenesis.

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Acknowledgements

We thank Graham Hardie and Simon Hawley (University of Dundee, Dundee, UK) for their helpful comments and valuable scientific input into our work and also for their kindness in providing us with different antibodies and reagents to measure the LKB1-controlled AMPK activity and to test the role of ΔN-LKB1 on different ARKs. We are also grateful to Christelle Forcet, Nicolas Aznar and Maya Ghawitian from Billaud’s laboratory for their help with the analysis of LKB1-induced polarizing activity. We are indebted to Benoit Viollet and Marc Foretz for providing us with AMPK plasmids and helpful discussions. We thank Pascal Maire (from Inserm U1016, Paris, France) and all people of the team for helpful discussions, suggestions and critical reading of the manuscript. We are grateful to Hélène Blons (HEGP, Paris, France) and Sylvie Grazzeri (Inserm U823, Grenoble, France) for providing the lung cancer cell lines and some lung tumors, respectively. We also thank Véronique Lenoir and Catherine Esnous for technical help in fatty acid oxidation experiments, and animal facility of Institut Cochin for maintenance of mouse colonies. Core fundings came from INSERM, grants from LNCC (France) ‘Equipe labèlisée Ligue Nationale Contre le Cancer’, INCA grants and LABEX Who amI?. RD was funded by an LNCC fellowship.

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Author notes

  1. R Dahmani and P-A Just: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm, U1016, Institut Cochin, Paris, France

    R Dahmani, P-A Just, F Canal, L Finzi, C Prip-Buus, M Lambert, P Sujobert, C Cavard, S Marmier, B Terris & C Perret

  2. Cnrs, UMR8104, Paris, France

    R Dahmani, P-A Just, F Canal, L Finzi, C Prip-Buus, M Lambert, P Sujobert, C Cavard, S Marmier, B Terris & C Perret

  3. Université Paris Descartes, Paris, France

    R Dahmani, P-A Just, F Canal, L Finzi, C Prip-Buus, M Lambert, P Sujobert, C Cavard, S Marmier, B Terris & C Perret

  4. Equipe labellisée LNCC, Paris, France

    R Dahmani, P-A Just, F Canal, L Finzi, C Cavard, S Marmier, B Terris & C Perret

  5. Institut Albert Bonniot, CRI Inserm/UJF U823, Rond Point de la Chantourne, La Tronche, France

    A Delay, K Buchet-Poyau & M Billaud

  6. Section of Cardiology, Boston University School of Medicine, Boston, MA, USA

    E Miller

  7. Pathology Unit, Hôpital Cochin, Paris, France

    B Terris

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  1. R Dahmani
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Correspondence to M Billaud or C Perret.

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Dahmani, R., Just, PA., Delay, A. et al. A novel LKB1 isoform enhances AMPK metabolic activity and displays oncogenic properties. Oncogene 34, 2337–2346 (2015). https://doi.org/10.1038/onc.2014.182

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