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: Yun-Rong Zhu, Yong Xu, Jian-Feng Fang, Feng Zhou, Xiong-Wei Deng, Yun-Qing Zhang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 451 Issue 1 Pg. 112-8 (Aug 15 2014) ISSN: 1090-2104 [Electronic] United States
• PMID: 25068992 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Bufanolides
• Cinnamates
• DDIT3 protein, human
• salubrinal
• Transcription Factor CHOP
• Caspase 12
• bufotalin
• Thiourea

Topics

• Animals
• Apoptosis (drug effects)
• Bone Neoplasms (drug therapy, metabolism, pathology)
• Bufanolides (pharmacology)
• Caspase 12 (metabolism)
• Cinnamates (pharmacology)
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum Stress (drug effects)
• Gene Silencing
• Humans
• Male
• Mice
• Mice, SCID
• Osteoblastoma (drug therapy, metabolism, pathology)
• Thiourea (analogs & derivatives, pharmacology)
• Transcription Factor CHOP (genetics, metabolism)
• Xenograft Model Antitumor Assays