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In vitro chemo- and radio-resistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways

Oncogene volume 21, pages 8683–8695 (2002)Cite this article

Abstract

Most small cell lung cancer (SCLC) patients relapse within 12 months of starting combination chemotherapy plus radio-therapy, due to the development of acquired chemo- and radio-resistance. This phenomenon relates to the induction of tumour differentiation, resulting in apoptosis-resistant, morphologically variant (v-SCLC) cells, which lack the neuroendocrine expression of classic (c-) SCLC cells. In this study spontaneously adherent SCLC sublines were shown by differential gene expression analysis to provide an in vitro model of variant differentiation in SCLC, with down-regulation of neuroendocrine markers and up-regulation of epithelial differentiation markers cyclin D1, endothelin, the cell adhesion molecules CD 44 and integrin subunits α2, β3 and β4. The sensitivity of adherent SCLC sublines to etoposide, cyclophosphamide and gamma radiation was significantly diminished relative to parent suspension cell lines. Western blot analysis using phosphorylation-specific antibodies to Akt and MAP kinase revealed markedly elevated activation in adherent SCLC sublines, paralleled by increased levels of phosphorylated Bad protein and activated NF-κB. Subcultivation of the adherent sublines on uncoated surfaces reversed their adherent phenotype immediately and under these conditions Akt activity reverted to low levels. These results suggest that c-SCLC cells can differentiate spontaneously to v-SCLC and that the associated cellular adhesion may trigger Akt-dependent inhibition of apoptosis in SCLC cells, thus leading to acquired chemo- and radio-resistance.

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Acknowledgements

We are most grateful to Dr Michael Kersting and Guido Piontek for invaluable technical assistance and to Dr Cornelia Brendel for kindly performing STR fingerprint analysis on classical and variant cell lines.

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Authors and Affiliations

  1. Department of Haematology and Oncology, Centre for Internal Medicine, University Hospital, Philipps-Universität Marburg, Marburg, D35033, Germany

    Alison C Kraus, Ines Ferber, Sven-Oliver Bachmann, Hannah Specht, Anja Wimmel & Marcus Schuermann

  2. Department of Radiotherapy and Radio-oncology, University Hospital, Philipps-Universität Marburg, Marburg, D35033, Germany

    Markus W Gross

  3. Department of Neuropathology, University Hospital, Philipps-Universität Marburg, Marburg, D35033, Germany

    Juergen Schlegel

  4. Institute for Molecular Biology and Tumour Research, University Hospital, Philipps-Universität Marburg, Marburg, D35033, Germany

    Guntram Suske

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  1. Alison C Kraus
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Correspondence to Marcus Schuermann.

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Kraus, A., Ferber, I., Bachmann, SO. et al. In vitro chemo- and radio-resistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways. Oncogene 21, 8683–8695 (2002). https://doi.org/10.1038/sj.onc.1205939

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