title: 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.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Junli
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Hongshen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Xianyang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Yimian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Zhilie
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Lu
authors.affiliation: The Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China; Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Zimmerman
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: yjwang8888@126.com.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopedics & Traumatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: yanpingyangks@163.com.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D019668:Liliaceae / Q000737:chemistry; D058990:Molecular Targeted Therapy; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C556217:polyphyllin I; D046988:Proteasome Endopeptidase Complex; D004144:Diosgenin
keywords: Apoptosis; Cell cycle; Epithelialmesenchymal transition; Osteosarcoma; Polyphyllin I; Proteasome activity