| Title | proteasome inhibition with bortezomib suppresses growth and induces apoptosis in osteosarcoma. | | Author(s) | Shapovalov Y, Benavidez D, Zuch D, Eliseev RA | | Institution | Center for Musculoskeletal Research, University of Rochester School of Medicine & Dentistry, Rochester, NY. | | Source | Int J Cancer 2009 Nov 5. | | Abstract | Osteosarcomas are primary bone tumors of osteoblastic origin that mostly affect adolescent patients. These tumors are highly aggressive and metastatic. Previous reports indicate that gain of function of a key osteoblastic differentiation factor, Runx2, leads to growth inhibition in osteosarcoma. We have previously established that Runx2 transcriptionally regulates expression of a major pro-apoptotic factor, Bax. Runx2 is regulated via proteasomal degradation, and proteasome inhibition has a stimulatory effect on Runx2. In this study, we hypothesized that proteasome inhibition will induce Runx2 and Runx2-dependent Bax expression sensitizing osteosarcoma cells to apoptosis. Our data showed that a proteasome inhibitor, bortezomib, increased Runx2 and Bax in osteosarcoma cells. In vitro, bortezomib suppressed growth and induced apoptosis in osteosarcoma cells but not in non-malignant osteoblasts. Experiments involving intratibial tumor xenografts in nude mice demonstrated significant tumor regression in bortezomib-treated animals. Immunohistochemical studies revealed that bortezomib inhibited cell proliferation and induced apoptosis in osteosarcoma xenografts. These effects correlated with increased immunoreactivity for Runx2 and Bax. In summary, our results indicate that bortezomib suppresses growth and induces apoptosis in osteosarcoma in vitro and in vivosuggesting that proteasome inhibition may be effective as an adjuvant to current treatment regimens for these tumors. (c) 2009 UICC. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19894220 |
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