title: BMPR2 inhibition induced apoptosis and autophagy via destabilization of XIAP in human chondrosarcoma cells.
abstract: Bone morphogenetic proteins (BMPs) are multifunctional proteins, and their receptors (BMPRs) have crucial roles in the process of signaling. However, their function in cancer is somewhat inconsistent. It has been demonstrated that more prevalent expression of bone morphogenetic protein receptor 2 (BMPR2) has been detected in dedifferentiated chondrosarcomas than conventional chondrosarcomas. Here, we find that BMPR2 inhibition induces apoptosis and autophagy of chondrosarcoma. We found that BMPR2 expression was correlated with the clinicopathological features of chondrosarcomas, and could predict the treatment outcome. Knockdown of BMPR2 by small interfering RNA results in growth inhibition in chondrosarcoma cells. Silencing BMPR2 promoted G2/M cell cycle arrest, induced chondrosarcoma cell apoptosis through caspase-3-dependent pathway via repression of X-linked inhibitor of apoptosis protein (XIAP) and induced autophagy of chondrosarcoma cells via XIAP-Mdm2-p53 pathway. Inhibition of autophagy induced by BMPR2 small interfering RNA (siBMPR2) sensitized chondrosarcoma cells to siBMPR2-induced apoptotic cell death, suggesting that autophagy has a protective role for chondrosarcoma cells in context of siBMPR2-induced apoptotic cell death. In vivo tumorigenicity assay in mice indicated that inhibition of BMPR2 reduced tumor growth. Taken together, our results suggest that BMPR2 has a significant role in the tumorigenesis of chondrosarcoma, and could be an important prognostic marker for chondrosarcoma. BMPR2 inhibition could eventually provide a promising therapy for chondrosarcoma treatment.
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, People's Republic of China.
authors.forename: G
authors.initials: G
authors.lastname: Jiao
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Guo
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, People's Republic of China.
authors.forename: T
authors.initials: T
authors.lastname: Ren
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, People's Republic of China.
authors.forename: Q
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Liang
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Ren
authors.affiliation: Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, People's Republic of China.
authors.forename: K
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Pathology, Peking University People's Hospital, Beijing 100044, People's Republic of China.
authors.forename: K
authors.initials: K
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009372:Neoplasms, Connective Tissue / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D052006:Bone Morphogenetic Protein Receptors, Type II; D053148:Caspase 3