Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone
| العنوان: | Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone |
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| المؤلفون: | Shiro Soga, Len Neckers, Akihiro Yano, Shinji Tsutsumi, Hiroyuki Osada, Min-Jung Lee, Jane B. Trepel |
| المصدر: | Proceedings of the National Academy of Sciences. 105:15541-15546 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Male, Lactams, Macrocyclic, Proto-Oncogene Proteins pp60(c-src), Osteoclasts, Bone Neoplasms, Biology, Hsp90 inhibitor, Osteoclast maturation, Mice, Prostate cancer, Osteoclast, Benzoquinones, polycyclic compounds, medicine, Animals, Immunoprecipitation, HSP90 Heat-Shock Proteins, Phosphorylation, Protein kinase B, Multidisciplinary, Carcinoma, Integrin beta3, Prostatic Neoplasms, Biological Sciences, medicine.disease, Mice, Inbred C57BL, Oncogene Protein v-akt, Dasatinib, medicine.anatomical_structure, Cancer cell, Cancer research, Signal Transduction, Proto-oncogene tyrosine-protein kinase Src, medicine.drug |
| الوصف: | Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Src-dependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c5f621428a36b318cb474874656742fd https://doi.org/10.1073/pnas.0805354105 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c5f621428a36b318cb474874656742fd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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