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RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

Oncogene volume 35, pages 1760–1769 (2016)Cite this article

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Abstract

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, which is mainly due to its high risk of metastatic dissemination. One critical point of this process is the ability of cancer cells to detach from the primary tumor and migrate through the extracellular matrix; however, the underlying molecular mechanisms are not yet fully understood. In the present study, we identified the small GTPase RhoB as a key regulator of bronchial cell morphology in a three-dimensional (3D) matrix. RhoB loss, which is frequently observed during lung cancer progression, induced an epithelial–mesenchymal transition (EMT) characterized by an increased proportion of invasive elongated cells in 3D. The process was mediated by Slug induction and E-cadherin repression. In addition, downregulation of RhoB induced Akt1 activation, which in turn activated Rac1 through the guanine-exchange factor Trio to control cell shape rearrangement. Further, we provide evidence that RhoB interacted with and positively regulates phosphatase PP2A through the recruitment of its regulatory subunit B55, which was found to be crucial for Akt dephosphorylation. B55 inhibition completely suppressed RhoB-mediated PP2A regulation. Finally, we show that PP2A inactivation, by targeting either its catalytic or its regulatory B55 subunit, completely reversed RhoB-dependent morphological changes and also fully prevented the ability of RhoB to decrease the invasiveness of bronchial cells. Altogether, these results highlight a novel signaling axis and describe new molecular mechanisms that could explain the tumor suppressor role of RhoB in lung cancer. Therefore, we propose that RhoB could be responsible for early metastatic prevention by inhibiting the EMT-derived invasiveness of lung cells through the control of PP2A activity.

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Acknowledgements

We are grateful to Professor Alain Puisieux (CRCL, Lyon, France) for his helpful comments on the manuscript. We thank Rémi Gence for helping with recombinant proteins. This work was supported by grants from INSERM (Institut National de la Santé et de la Recherche Médicale), Groupe de Recherche Institut Claudius Regaud, the Foundation Recherche et Innovation Thérapeutique en Cancérologie and INCa (Institut National du Cancer) France.

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  1. E Bousquet and O Calvayrac: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm, UMR 1037-CRCT, Toulouse, France

    E Bousquet, O Calvayrac, J Mazières, I Lajoie-Mazenc, N Boubekeur, G Favre & A Pradines

  2. Université Paul Sabatier, Toulouse, France

    E Bousquet, O Calvayrac, J Mazières, I Lajoie-Mazenc, N Boubekeur, G Favre & A Pradines

  3. Département de Biologie, Institut Claudius Regaud, Toulouse, France

    E Bousquet, O Calvayrac, I Lajoie-Mazenc, N Boubekeur, G Favre & A Pradines

  4. Hôpital Larrey Département de Pneumologie, CHU Toulouse, Toulouse, France

    J Mazières

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Bousquet, E., Calvayrac, O., Mazières, J. et al. RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition. Oncogene 35, 1760–1769 (2016). https://doi.org/10.1038/onc.2015.240

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