title: Proteasome inhibition with bortezomib suppresses growth and induces apoptosis in osteosarcoma.
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 proapoptotic 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 nonmalignant 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 vivo suggesting that proteasome inhibition may be effective as an adjuvant to current treatment regimens for these tumors. Published 2009 UICC. This article is a US Government work and, as such, is in the public domain in the United States of America.
authors.affiliation: Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Shapovalov
authors.forename: David
authors.initials: D
authors.lastname: Benavidez
authors.forename: Daniel
authors.initials: D
authors.lastname: Zuch
authors.forename: Roman A
authors.initials: RA
authors.lastname: Eliseev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000473:pathology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D017931:DNA Primers; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib