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RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation

Walsh, Naomi and Larkin, Anne-Marie and Swan, Niall and Conlon, Kevin and Dowling, Paul and McDermott, Ray and Clynes, Martin (2011) RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation. Cancer Letters, 306 (2). pp. 180-189. ISSN 0304-3835

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Abstract

We previously identified Hop as over expressed in invasive pancreatic cancer cell lines and malignant tissues of pancreatic cancer patients, suggesting an important role for Hop in the biology of invasive pancreatic cancer. Hop is a co-chaperone protein that binds to both Hsp70/Hsp90. We hypothesised that by targeting Hop, signalling pathways modulating invasion and client protein stabilisation involving Hsp90-dependent complexes may be altered. In this study, we show that Hop knockdown by small interfering (si)RNA reduces the invasion of pancreatic cancer cells, resulting in decreased expression of the downstream target gene, matrix metalloproteinases-2 (MMP-2). Hop in conditioned media co-immunoprecipitates with MMP-2, implicating a possible extracellular function for Hop. Knockdown of Hop expression also reduced expression levels of Hsp90 client proteins, HER2, Bcr-Abl, c-MET and v-Src. Furthermore, Hop is strongly expressed in high grade PanINs compared to lower PanIN grades, displaying differential localisation in invasive ductal pancreatic cancer, indicating that the localisation of Hop is an important factor in pancreatic tumours. Our data suggests that the attenuation of Hop expression inactivates key signal transduction proteins which may decrease the invasiveness of pancreatic cancer cells possibly through the modulation of Hsp90 activity. Therefore, targeting Hop in pancreatic cancer may constitute a viable strategy for targeted cancer therapy.

Item Type:Article (Published)
Refereed:Yes
Uncontrolled Keywords:Hop (Hsp90/Hsp70 Organising protein)/ STIP1 (Stress induced phosphoprotein 1); MMP2; pancreatic cancer; invasion; Hsp90
Subjects:Biological Sciences > Cell biology
Medical Sciences > Cancer
DCU Faculties and Centres:Research Initiatives and Centres > National Institute for Cellular Biotechnology (NICB)
Publisher:Elsevier
Official URL:http://dx.doi.org/10.1016/j.canlet.2011.03.004
Copyright Information:© 2011 Elsevier
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 License. View License
ID Code:16871
Deposited On:26 Mar 2012 11:54 by Naomi Walsh. Last Modified 26 Mar 2012 11:54

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