An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis

Lara, R, Mauri, F A, Taylor, H, Derua, R, Shia, A, Gray, C, Nicols, A, Shiner, R J, Schofield, E, Bates, P A, Waelkens, E, Dallman, M, Lamb, J, Zicha, D, Downward, J, Seckl, M J and Pardo, O E (2011) An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis. Oncogene, 30 (32). pp. 3513-3521. ISSN 1476-5594

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Abstract

We performed a kinome-wide siRNA screen and identified 70 kinases altering cell migration in A549 lung cancer cells. In particular, ribosomal S6 kinase 1 (RSK1) silencing increased, whereas RSK2 and RSK4 downregulation inhibited cell motility. In a secondary collagen-based three-dimensional invasion screen, 38 of our hits cross-validated, including RSK1 and RSK4. In two further lung cancer cell lines, RSK1 but not RSK4 silencing showed identical modulation of cell motility. We therefore selected RSK1 for further investigation. Bioinformatic analysis followed by co-immunoprecipitation-based validation revealed that the actin regulators VASP and Mena interact with RSK1. Moreover, RSK1 phosphorylated VASP on T278, a site regulating its binding to actin. In addition, silencing of RSK1 enhanced the metastatic potential of these cells in vivo using a zebrafish model. Finally, we investigated the relevance of this finding in human lung cancer samples. In isogenically matched tissue, RSK1 was reduced in metastatic versus primary lung cancer lesions. Moreover, patients with RSK1-negative lung tumours showed increased number of metastases. Our results suggest that the findings of our high-throughput in vitro screen can reliably identify relevant clinical targets and as a proof of principle, RSK1 may provide a biomarker for metastasis in lung cancer patients.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: Q Science
Q Science > QM Human anatomy
Q Science > QR Microbiology
R Medicine
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens > RC0280 By region, system, or organ of the body, or type of tumor, A-Z
Depositing User: Tracey O'Gorman
Date Deposited: 02 Nov 2012 16:49
Last Modified: 14 May 2015 09:45
URI: http://sro.sussex.ac.uk/id/eprint/42059
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