title: Bufotalin-induced apoptosis in osteoblastoma cells is associated with endoplasmic reticulum stress activation.
abstract: The search for novel and more efficient chemo-agents against malignant osteoblastoma is important. In this study, we examined the potential anti-osteoblastoma function of bufotalin, and studied the underlying mechanisms. Our results showed that bufotalin induced osteoblastoma cell death and apoptosis in dose- and time-dependent manners. Further, bufotalin induced endoplasmic reticulum (ER) stress activation in osteoblastoma cells, the latter was detected by the induction of C/EBP homologous protein (CHOP), phosphorylation of inositol-requiring enzyme 1 (IRE1) and PKR-like endoplasmic reticulum kinase (PERK), as well as caspase-12 activation. Conversely, the ER stress inhibitor salubrinal, the caspase-12 inhibitor z-ATAD-fmk as well as CHOP depletion by shRNA significantly inhibited bufotalin-induced osteoblastoma cell death and apoptosis. Finally, by using a mice xenograft model, we demonstrated that bufotalin inhibited U2OS osteoblastoma cell growth in vivo. In summary, our results suggest that ER stress contributes to bufotalin-induced apoptosis in osteoblastoma cells. Bufotalin might be investigated as a novel anti-osteoblastoma agent.
authors: Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, Jiangsu 214400, China.
authors: Yun-Rong
authors: YR
authors: Zhu
authors: Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215000, China.
authors: Yong
authors: Y
authors: Xu
authors: Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, Jiangsu 214400, China.
authors: Jian-Feng
authors: JF
authors: Fang
authors: Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, Jiangsu 214400, China.
authors: Feng
authors: F
authors: Zhou
authors: Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, Jiangsu 214400, China.
authors: Xiong-Wei
authors: XW
authors: Deng
authors: Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, Jiangsu 214400, China. Electronic address: yunqingzhang@126.com.
authors: Yun-Qing
authors: YQ
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002018:Bufanolides / Q000494:pharmacology*; D053454:Caspase 12 / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018215:Osteoblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D002018:Bufanolides; D002934:Cinnamates; C497249:DDIT3 protein, human; C496827:salubrinal; D051742:Transcription Factor CHOP; D053454:Caspase 12; C004600:bufotalin; D013890:Thiourea
keywords: Apoptosis and signaling; Bufotalin; ER stress; Osteoblastoma