Molecular mechanisms of Polyphyllin I-induced apoptosis and reversal of the epithelial-mesenchymal transition in human osteosarcoma cells.

Abstract

Osteosarcoma is a most common highly malignant bone tumor in children and adolescents. Polyphyllin I (PPI) is an ethanol extraction from Paris polyphylla Smith var.yunnanensis (Franch.) Hand.-Mazz, which belongs to antipyretic-detoxicate family and has been used as a natural medicine in the treatment of infectious disease and cancer in China for centuries. The proteasome activity inhibitory and anti-osteosarcoma effects of PPI have not been known. Here we found PPI exhibited a selective inhibitory effect on proteasomal chymotrypsin (CT)-like activity, both in purified human proteasome and in cultured osteosarcoma cellular proteasome, and caused an accumulation of ubiquitinated proteins. PPI also inhibited viability, proliferation, migration, and invasion of MG-63, Saos-2, and U-2 OS osteosarcoma cells and resulted in S phase arrest and apoptosis. Furthermore, we explored the molecular targets involved. Exposure of osteosarcoma cells to PPI caused an inactivation of the intrinsic nuclear factor κB (NF-κB) and activation of unfolded protein response (UPR)/endoplasmic reticulum (ER) stress signaling cascade in osteosarcoma cells, followed by down-regulation of anti-apoptotic proteins, with up-regulation of pro-apoptotic proteins. We also demonstrated down-regulation of c-Myc, Cyclin B1, Cyclin D1, and CDK1, which are involved in the cell cycle and growth. Finally, we identified down-regulation of Vimentin, Snail, Slug, and up-regulation of E-cadherin, which are integral proteins involved in epithelial-mesenchymal transition (EMT). Taken together, our data provide insights into the mechanism underlying the anticancer activity of PPI in human osteosarcoma cells.

• Authors: Junli Chang, Hongshen Wang, Xianyang Wang, Yongjian Zhao, Dongfeng Zhao, Chenglong Wang, Yimian Li, Zhilie Yang, Sheng Lu, Qinghua Zeng, Jacquelyn Zimmerman, Qi Shi, Yongjun Wang, Yanping Yang
• Journal: Journal of ethnopharmacology (J Ethnopharmacol) Vol. 170 Pg. 117-27 (Jul 21 2015) ISSN: 1872-7573 [Electronic] Ireland
• PMID: 25978954 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Apoptosis Regulatory Proteins
• polyphyllin I
• Proteasome Endopeptidase Complex
• Diosgenin

Topics

• Antineoplastic Agents, Phytogenic (isolation & purification, pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Bone Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Diosgenin (analogs & derivatives, isolation & purification, pharmacology)
• Down-Regulation (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Humans
• Liliaceae (chemistry)
• Molecular Targeted Therapy
• Osteosarcoma (drug therapy, pathology)
• Proteasome Endopeptidase Complex (drug effects, metabolism)
• Up-Regulation (drug effects)