YM155, a survivin suppressant, triggers PARP-dependent cell death (parthanatos) and inhibits esophageal squamous-cell carcinoma xenografts in mice

Nan Zhao; Yousheng Mao; Gaijing Han; Qiang Ju; Lanping Zhou; Fang Liu; Yang Xu; Xiaohang Zhao

doi:10.18632/oncotarget.4315

YM155, a survivin suppressant, triggers PARP-dependent cell death (parthanatos) and inhibits esophageal squamous-cell carcinoma xenografts in mice

Oncotarget. 2015 Jul 30;6(21):18445-59. doi: 10.18632/oncotarget.4315.

Authors

Nan Zhao¹, Yousheng Mao², Gaijing Han¹, Qiang Ju¹, Lanping Zhou¹, Fang Liu¹, Yang Xu¹, Xiaohang Zhao¹

Affiliations

¹ State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
² Department of Thoracic Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Abstract

Here we demonstrated that sepantronium bromide (YM155), a survivin suppressant, inhibited esophageal squamous-cell carcinoma (ESCC) growth in mice bearing human ESCC xenografts without affecting body weight. In cell culture, YM155 decreased survivin levels and caused PARP-1 activation, poly-ADP polymer formation, and AIF translocation from the cytosol to the nucleus. Genetic knockdown of PARP-1 or AIF abrogated YM155-induced parthanatos cell death. Furthermore, FOS, JUN and c-MYC gene transcription, which is stimulated by activated PARP-1, was increased following YM155 treatment. Our data demonstrate that YM155 did not trigger apoptosis, but induced parthanatos, a cell death dependent on PARP-1 hyper-activation, and support clinical development of YM155 in ESCC.

Keywords: PARP; chemotherapy; esophageal cancer; parthanatos.

Publication types

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

MeSH terms

Animals
Blotting, Western
Carcinoma, Squamous Cell / drug therapy*
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism
Cell Death / drug effects
Cell Death / genetics
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
Dose-Response Relationship, Drug
Esophageal Neoplasms / drug therapy*
Esophageal Neoplasms / genetics
Esophageal Neoplasms / metabolism
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
Humans
Imidazoles / pharmacology*
Inhibitor of Apoptosis Proteins / antagonists & inhibitors
Mice, Nude
Microscopy, Electron, Transmission
Microscopy, Fluorescence
Naphthoquinones / pharmacology*
Oligonucleotide Array Sequence Analysis
Poly(ADP-ribose) Polymerases / genetics
Poly(ADP-ribose) Polymerases / metabolism*
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Survivin
Tumor Burden / drug effects
Tumor Burden / genetics
Xenograft Model Antitumor Assays*

Substances

BIRC5 protein, human
Imidazoles
Inhibitor of Apoptosis Proteins
Naphthoquinones
Survivin
Poly(ADP-ribose) Polymerases
sepantronium