FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells

Li Zhang; Handong Wang; Ke Ding; Jianguo Xu

doi:10.1016/j.toxlet.2015.04.015

FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells

Toxicol Lett. 2015 Jul 2;236(1):43-59. doi: 10.1016/j.toxlet.2015.04.015. Epub 2015 May 1.

Authors

Li Zhang¹, Handong Wang², Ke Ding¹, Jianguo Xu¹

Affiliations

¹ Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.
² Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China. Electronic address: njhdwang@hotmail.com.

PMID: 25939952
DOI: 10.1016/j.toxlet.2015.04.015

Abstract

FTY720 is a potent immunosuppressant which has preclinical antitumor efficacy in various cancer models. However, its role in glioblastoma remains unclear. In the present study, we found that FTY720 induced extrinsic apoptosis, necroptosis and autophagy in human glioblastoma cells. Inhibition of autophagy by either RNA interference or chemical inhibitors attenuated FTY720-induced apoptosis and necrosis. Furthermore, autophagy, apoptosis and necrosis induction were dependent on reactive oxygen species-c-Jun N-terminal kinase-protein 53 (ROS-JNK-p53) loop mediated phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin/p70S6 kinase (PI3K/AKT/mTOR/p70S6K) pathway. In addition, receptor-interacting protein 1 and 3 (RIP1 and RIP3) served as an upstream of ROS-JNK-p53 loop. However, the phosphorylation form of FTY720 induced autophagy but not apoptosis and necroptosis. Finally, the in vitro results were validated in vivo in xenograft mouse of glioblastoma cells. In conclusion, the current study provided novel insights into understanding the mechanisms and functions of FTY720-induced apoptosis, necroptosis and autophagy in human glioblastoma cells.

Keywords: Apoptosis; Autophagy; FTY720; Glioblastoma; Necroptosis.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects*
Apoptosis Regulatory Proteins / antagonists & inhibitors
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism
Autophagy / drug effects*
Beclin-1
Biomarkers / metabolism
Cell Line, Tumor
Dose-Response Relationship, Drug
Fingolimod Hydrochloride
Glioblastoma / drug therapy*
Glioblastoma / metabolism
Glioblastoma / pathology
Humans
Male
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice, Nude
Necrosis
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Propylene Glycols / administration & dosage
Propylene Glycols / pharmacology
Propylene Glycols / therapeutic use*
RNA Interference
Reactive Oxygen Species / metabolism
Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
Signal Transduction / drug effects*
Sphingosine / administration & dosage
Sphingosine / analogs & derivatives*
Sphingosine / pharmacology
Sphingosine / therapeutic use
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Apoptosis Regulatory Proteins
BECN1 protein, human
Beclin-1
Biomarkers
Membrane Proteins
Neoplasm Proteins
Propylene Glycols
Reactive Oxygen Species
RIPK1 protein, human
RIPK3 protein, human
Receptor-Interacting Protein Serine-Threonine Kinases
Fingolimod Hydrochloride
Sphingosine