Heat shock cognate 70 protein secretion as a new growth arrest signal for cancer cells

• Published in: Oncogene Vol. 29; no. 1; pp. 117 - 127
• Main Authors: Nirdé, P, Derocq, D, Maynadier, M, Chambon, M, Basile, I, Gary-Bobo, M, Garcia, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.01.2010; Nature Publishing Group; Nature Publishing Group [1987-....]
• Subjects: Animals; Apoptosis; Biological and medical sciences; Blotting, Western; Breast Neoplasms; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - physiopathology; Cancer; Cancer cells; Cathepsin D; Cathepsin D - genetics; Cathepsin D - metabolism; Cell Biology; Cell Count; Cell growth; Cell Line; Cell Line, Tumor; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular Biology; Chromatography, High Pressure Liquid; Culture Media, Serum-Free; Culture Media, Serum-Free - pharmacology; Electrophoresis, Polyacrylamide Gel; Female; Fundamental and applied biological sciences. Psychology; Genetics; Health aspects; Heat shock proteins; HSC70 Heat-Shock Proteins; HSC70 Heat-Shock Proteins - genetics; HSC70 Heat-Shock Proteins - metabolism; HSC70 Heat-Shock Proteins - secretion; Human Genetics; Humans; Internal Medicine; Life Sciences; Medicine; Medicine & Public Health; Microscopy, Electron, Scanning; Molecular and cellular biology; Neoplasms; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - physiopathology; Oncology; original-article; Physiological aspects; Recombinant Proteins; Recombinant Proteins - pharmacology; RNA Interference; Secretion. Exocytosis; Signal Transduction; Signal Transduction - drug effects; Signal Transduction - physiology; France; extracellular; cancer; secretion; growth inhibition; cathepsin D; Hsc70; Shock; Enzyme; Growth; Secretion; Malignant tumor; Carcinogenesis; Extracellular; Protein; Peptidases; Hydrolases; Aspartic endopeptidases; Cathepsin D; Inhibition; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.311

Earlier studies indicated that density-arrested cancer cells released an unidentified growth inhibitor whose secretion was prevented by overexpression of the lysosomal protease cathepsin D (cath D). In this study, this growth inhibitor was purified by affinity chromatography and identified as the heat shock cognate 70 protein (hsc70) based on its peptide microsequencing and specific antibody recognition. Among intracellular proteins, including other heat shock proteins, only constitutive hsc70 was secreted in response to the high-cell density. Moreover, hsc70 secretion from cancer cells was generated by serum deprivation, whereas its cellular concentration did not change. Prevention of Hsc70 secretion by cath D overexpression was associated with the formation of multilayer cell cultures, thus indicating a loss of contact inhibition. In addition, we showed that supplementing the culture medium with purified hsc70 inhibited cell proliferation in the nanomolar range. Conversely, removal of this extracellular hsc70 from the medium by either retention on ADP-agarose or competition at the Hsc70 binding site restored cell proliferation. Hsc70 appears active in human breast cancer cells and hypersecreted by direct cath D inhibition. These results suggest a new role of this secreted hsc70 chaperone in cell proliferation that might account for the higher tumor growth of cancer cells overexpressing cath D.