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Mol Cell Proteomics. 2014 Dec;13(12):3585-601. doi: 10.1074/mcp.M114.041228. Epub 2014 Oct 2.

The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets.

Author information

1
From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France; ¶Aix-Marseille Université, F-13284, Marseille, France; ‖CNRS, UMR7258, CRCM, Marseille, F-13009, France;
2
¶Aix-Marseille Université, F-13284, Marseille, France; **Institut de Mathématiques de Marseille, CNRS UMR7373, Marseille, F-13009, France;
3
From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France;
4
‡‡Inserm U866, Faculty of Medicine, 21000 Dijon, France; §§CGFL Dijon, France;
5
¶Aix-Marseille Université, F-13284, Marseille, France; ¶¶TAGC Inserm U1090, Marseille, F-13009, France; ‖‖CNRS, France.
6
From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France; ¶Aix-Marseille Université, F-13284, Marseille, France; ‖CNRS, UMR7258, CRCM, Marseille, F-13009, France; palma.rocchi@inserm.fr.

Abstract

Previously, we identified the stress-induced chaperone, Hsp27, as highly overexpressed in castration-resistant prostate cancer and developed an Hsp27 inhibitor (OGX-427) currently tested in phase I/II clinical trials as a chemosensitizing agent in different cancers. To better understand the Hsp27 poorly-defined cytoprotective functions in cancers and increase the OGX-427 pharmacological safety, we established the Hsp27-protein interaction network using a yeast two-hybrid approach and identified 226 interaction partners. As an example, we showed that targeting Hsp27 interaction with TCTP, a partner protein identified in our screen increases therapy sensitivity, opening a new promising field of research for therapeutic approaches that could decrease or abolish toxicity for normal cells. Results of an in-depth bioinformatics network analysis allying the Hsp27 interaction map into the human interactome underlined the multifunctional character of this protein. We identified interactions of Hsp27 with proteins involved in eight well known functions previously related to Hsp27 and uncovered 17 potential new ones, such as DNA repair and RNA splicing. Validation of Hsp27 involvement in both processes in human prostate cancer cells supports our system biology-predicted functions and provides new insights into Hsp27 roles in cancer cells.

PMID:
25277244
PMCID:
PMC4256507
DOI:
10.1074/mcp.M114.041228
[Indexed for MEDLINE]
Free PMC Article

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