title: Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma.
abstract: Bortezomib, formerly known as PS341, is a novel proteasome inhibitor with in vitro and in vivo antineoplastic effects in many malignancies. However, diverse antitumor mechanisms of bortezomib have been identified in many investigations and preclinical studies. Understanding the molecular and cellular mechanisms through which bortezomib acts will improve the therapeutic utility of this drug in different cancer types. In the present study, we investigated the in vitro and in vivo effects of bortezomib on chondrosarcoma. Bortezomib selectively inhibited cell growth in chondrosarcoma cells but not in normal articular cartilage cells. In addition to growth inhibition, apoptosis and cell cycle arrest, bortezomib triggered alleviation of migratory and invasive properties of chondrosarcoma cells. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream targets Bcl-2, cyclin D1 and c-Myc was inactivated by bortezomib treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced bortezomib-induced apoptosis, and concomitantly enhanced the inhibitory effect of bortezomib on cell viability, migration and invasion. Moreover, while Slug, MMP9, MMP2, CD44, N-cadherin and vimentin, the mesenchymal cell markers, were repressed by bortezomib concomitant increased expression of E-cadherin was observed. In vivo, bortezomib downregulated Stat3 activity and mesenchymal cell marker expression, induced apoptosis and inhibition of metastasis and tumor growth. Together, inactivation of Stat3 signaling contributes to bortezomib-induced inhibition of tumor growth, migration and invation on chondrosarcoma. Bortezomib demonstrates an antineoplastic role on chondrosarcoma both in vitro and in vivo. These beneficial effects can be explained by bortezomib-mediated Stat3 supression. The present study suggests a promising therapeutics target in chondrosarcoma and probably in other kinds of metastatic malignant tumors.
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Bao
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, P.R. China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Ren
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, P.R. China.
authors.forename: Chongmin
authors.initials: C
authors.lastname: Ren
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, P.R. China.
authors.forename: Kang
authors.initials: K
authors.lastname: Yang
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, P.R. China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000473:pathology*; D000069286:Bortezomib / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002813:Chondrosarcoma / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000069286:Bortezomib