The ERK/eIF4F/Bcl-XL pathway mediates SGP-2 induced osteosarcoma cells apoptosis in vitro and in vivo

Zhenzhen Zhang; Ying Zheng; Rui Zhu; Yiqing Zhu; Wenbing Yao; Wei Liu; Xiangdong Gao

doi:10.1016/j.canlet.2014.06.015

The ERK/eIF4F/Bcl-XL pathway mediates SGP-2 induced osteosarcoma cells apoptosis in vitro and in vivo

Cancer Lett. 2014 Oct 1;352(2):203-13. doi: 10.1016/j.canlet.2014.06.015. Epub 2014 Jul 12.

Authors

Zhenzhen Zhang¹, Ying Zheng¹, Rui Zhu¹, Yiqing Zhu¹, Wenbing Yao¹, Wei Liu², Xiangdong Gao¹

Affiliations

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Jiangsu, China; School of Life Science and Technology, China Pharmaceutical University, Jiangsu, China.
² State Key Laboratory of Natural Medicines, China Pharmaceutical University, Jiangsu, China; School of Life Science and Technology, China Pharmaceutical University, Jiangsu, China; Department of Food Quality and Safety, China Pharmaceutical University, Jiangsu, China.

PMID: 25025927
DOI: 10.1016/j.canlet.2014.06.015

Abstract

The aim of this study is to assess the molecular foundation of anti-tumor activity of SGP-2 in osteosarcoma cells. SGP-2 significantly blocks cell proliferation in human osteosarcoma U2OS cell model and inhibits tumor growth without causing apparent toxicity effect in mouse sarcoma S-180 cell-derived tumor model. Moreover, SGP-2 induces intrinsic apoptosis including the activation of caspase-3/7/9, the loss of mitochondrial transmembrane potential (ΔΨm), and the release of cytochrome c from mitochondrion, controlled by the down-regulation of B-cell lymphoma-extra large (Bcl-XL). Further research reveals that SGP-2 inhibits the assembly of eukaryotic initiation factor 4F (eIF4F) complex which is responsible for the decline of Bcl-XL. Finally, extracellular-signal-regulated kinase (ERK) controls SGP-2 induced intrinsic apoptosis. Taken together, SGP-2 exerts anti-tumor effect through intrinsic apoptotic pathway controlled by ERK/eIF4F/Bcl-XL pathway.

Keywords: Apoptosis; ERK; Osteosarcoma; eIF4F.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / pharmacology*
Antineoplastic Agents, Phytogenic / toxicity
Apoptosis / drug effects*
Bone Neoplasms / drug therapy*
Bone Neoplasms / genetics
Bone Neoplasms / metabolism
Bone Neoplasms / pathology
Caspases / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Enzyme Activation
Eukaryotic Initiation Factor-4F / genetics
Eukaryotic Initiation Factor-4F / metabolism*
Extracellular Signal-Regulated MAP Kinases / metabolism*
Humans
Male
Membrane Potential, Mitochondrial / drug effects
Mice
Mice, Inbred ICR
Osteosarcoma / drug therapy*
Osteosarcoma / genetics
Osteosarcoma / metabolism
Osteosarcoma / pathology
Polysaccharides / pharmacology*
Polysaccharides / toxicity
RNA Interference
Signal Transduction / drug effects
Time Factors
Transfection
Tumor Burden / drug effects
bcl-X Protein / genetics
bcl-X Protein / metabolism*

Substances

Antineoplastic Agents, Phytogenic
BCL2L1 protein, human
Eukaryotic Initiation Factor-4F
Polysaccharides
bcl-X Protein
Extracellular Signal-Regulated MAP Kinases
Caspases