IGFBP-3 binds GRP78, stimulates autophagy and promotes the survival of breast cancer cells exposed to adverse microenvironments
| Autor: | Robert C. Baxter, Sue M. Firth, S. Grkovic, M. Hong, V.C. O'Reilly, S Han |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Small interfering RNA medicine.medical_treatment Breast Neoplasms Biology Autophagy Tumor Microenvironment Genetics medicine Animals Humans Endoplasmic Reticulum Chaperone BiP Molecular Biology Heat-Shock Proteins Tumor microenvironment Endoplasmic reticulum Growth factor HEK 293 cells Survival Analysis Cell biology HEK293 Cells Insulin-Like Growth Factor Binding Protein 3 MCF-7 Cells Unfolded protein response Female Signal transduction Signal Transduction |
| Zdroj: | Oncogene. 32:2412-2420 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2012.264 |
| Popis: | Despite the established role of insulin-like growth factor binding protein-3 (IGFBP-3) as a growth inhibitor in vitro, a high level of IGFBP-3 in breast tumor tissue is associated with the stimulation of xenograft growth in mice and poor prognosis in patients. To understand the contribution of IGFBP-3 to breast cancer progression, tandem affinity purification was used to identify novel interacting proteins. The endoplasmic reticulum protein, glucose-regulated protein 78 (GRP78), was shown to bind to IGFBP-3, confirmed by colocalization, coimmunoprecipitations, glutathione S-transferase (GST) pulldowns and a nanomolar binding affinity. GST pulldowns also indicated that the GRP78 ATPase domain mediated the interaction with IGFBP-3. The critical roles of GRP78 in the unfolded protein response and macroautophagy led to an investigation of possible links between IGFBP-3, GRP78 and cellular stress responses. IGFBP-3 was found to stimulate the survival of breast cancer cells subjected to glucose starvation and hypoxia. Pharmacological inhibitors and small interfering RNA knockdown established that the increased survival of IGFBP-3-expressing cells was dependent on an intact autophagy response, as well as GRP78. The contribution of autophagy was confirmed by the demonstration that IGFBP-3 expression increases both the formation of autophagic puncta and flux through the system. In conclusion, we have shown that IGFBP-3 stimulates autophagy and thereby promotes the survival of breast cancer cells exposed to conditions that represent the adverse microenvironments encountered by solid tumor cells in vivo. |
| Databáze: | OpenAIRE |
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