Abstract
Cdc37 is a 50 kDa molecular chaperone which targets intrinsically unstable protein kinases to the molecular chaperone HSP90. It is also an over-expressed oncoprotein that mediates carcinogenesis and maintenance of the malignant phenotype by stabilizing the compromised structures of mutant and/or over-expressed oncogenic kinases. Here we report that Cdc37 is not restricted intracellularly but instead it is also present on the surface of MDA-MB-453 and MDA-MB-231 human breast cancer cells, where it is shown to participate in cancer cell motility processes. Furthermore, we demonstrate using an anti-Cdc37 cell impermeable antibody, that similarly to its intracellular counterpart, this surface pool of Cdc37 specifically interacts with HSP90 as well as the kinase receptors HER2 and EGFR on the cell surface, probably acting as a co-factor in HSP90's extracellular chaperoning activities. Finally, we show that functional inhibition of surface HSP90 using mAb 4C5, a cell impermeable monoclonal antibody against this protein, leads not only to disruption of the Cdc37/HSP90 complex but also to inhibition of the Cdc37/ErbB receptors complexes. These results support an essential role for surface Cdc37 in concert with HSP90 on the cell surface during cancer cell invasion processes and strengthen the therapeutic potential of mAb 4C5 for the treatment of cancer.
Highlights
HSP90 is a molecular chaperone that functions in association with a cohort of co-chaperones to guide the stabilization and activation of an array of signaling proteins, including oncogenic kinases, transcription factors and hormone receptors [1,2]
Surface Cdc37 is involved in breast cancer cell motility Having established that the anti-Cdc37 antibody is not internalized but instead remains bound to the cellsurface when incubated with living MDA-MB-453 and MDA-MB231 cells, we examined the possible involvement of surface Cdc37 on the motility of these breast cancer cells, using the wound healing assay
In the present work we demonstrate that the co-chaperone Cdc37 is localized on the surface of MDA-MB-453 and MDAMB-231 breast cancer cells, where it is necessary for the motility of these cells and to its intracellular counterpart it interacts with the molecular chaperone HSP90
Summary
HSP90 is a molecular chaperone that functions in association with a cohort of co-chaperones to guide the stabilization and activation of an array of signaling proteins, including oncogenic kinases, transcription factors and hormone receptors [1,2]. Cdc mediates the formation of HSP90-Raf1 [9] and HSP90-Cdk complexes [10] and these interactions are necessary for protein stability and kinase function. Cdc, is increased in proliferating tissues, and is heavily expressed in certain cancers including anaplastic large cell lymphoma [18] acute myelocytic leukaemia [19], hepatocellular carcinoma [20] and multiple myeloma [21]. The platelet-derived growth factor receptor alpha which is up-regulated and activated in several malignancies forms a complex with HSP90 and the cochaperone Cdc in ovarian, glioblastoma, and lung cancer cells [24]. Together, these results support the targeting of Cdc for cancer therapy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
