Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways

Hsiao Yen Hsieh, Cheng Huang Shen, Ru Inn Lin, Yu Min Feng, Shih Yuan Huang, Yuan Hung Wang, Shu Fen Wu, Cheng Da Hsu, Michael W Y Chan

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Cyproheptadine, a serotonin antagonist, has recently been reported to function as a novel therapeutic agent by inhibiting PI3K/AKT signaling in several human cancers. However, the therapeutic effect of cyproheptadine in urothelial carcinoma (UC) has never been explored. In this study, we determined the effect of cyproheptadine on the growth of five human UC cell lines and an in vivo xenograft model. The results showed that cyproheptadine exerted an inhibitory effect on the proliferation of UC cells both in vitro and in vivo. Cyproheptadine also induced cell cycle arrest in the G1 phase, subsequently followed by apoptosis and necrosis. The underlying mechanisms of cell cycle arrest were associated with the reduction of c-Myc, induction of p21 and p27, and the stabilization of Rb expression. In addition, the suppression of the GSK3β/TSC2/mTOR pathway and deregulation of the GSK3β/β-catenin signaling were observed in cyproheptadine-treated UC cells. Furthermore, cyproheptadine-induced apoptosis was associated with ANGPTL4 expression followed by activation of caspase3 and PARP in UC cells. Our experimental results provide evidence that cyproheptadine is a suitable therapeutic agent for the treatment of UC.

Original languageEnglish
Pages (from-to)56-65
Number of pages10
JournalCancer Letters
Volume370
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

Fingerprint

Cyproheptadine
Catenins
Carcinoma
Cell Cycle Checkpoints
Apoptosis
Serotonin Antagonists
G1 Phase
Therapeutic Uses
Phosphatidylinositol 3-Kinases
Heterografts
Necrosis
Cell Line

Keywords

  • ANGPTL4
  • Cyproheptadine
  • mTOR signaling
  • Urothelial carcinoma
  • Wnt/β-catenin signaling

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways. / Hsieh, Hsiao Yen; Shen, Cheng Huang; Lin, Ru Inn; Feng, Yu Min; Huang, Shih Yuan; Wang, Yuan Hung; Wu, Shu Fen; Hsu, Cheng Da; Chan, Michael W Y.

In: Cancer Letters, Vol. 370, No. 1, 01.01.2016, p. 56-65.

Research output: Contribution to journalArticle

Hsieh, Hsiao Yen ; Shen, Cheng Huang ; Lin, Ru Inn ; Feng, Yu Min ; Huang, Shih Yuan ; Wang, Yuan Hung ; Wu, Shu Fen ; Hsu, Cheng Da ; Chan, Michael W Y. / Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways. In: Cancer Letters. 2016 ; Vol. 370, No. 1. pp. 56-65.
@article{e1fc3617a026415994aa45a933c3d6c1,
title = "Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways",
abstract = "Cyproheptadine, a serotonin antagonist, has recently been reported to function as a novel therapeutic agent by inhibiting PI3K/AKT signaling in several human cancers. However, the therapeutic effect of cyproheptadine in urothelial carcinoma (UC) has never been explored. In this study, we determined the effect of cyproheptadine on the growth of five human UC cell lines and an in vivo xenograft model. The results showed that cyproheptadine exerted an inhibitory effect on the proliferation of UC cells both in vitro and in vivo. Cyproheptadine also induced cell cycle arrest in the G1 phase, subsequently followed by apoptosis and necrosis. The underlying mechanisms of cell cycle arrest were associated with the reduction of c-Myc, induction of p21 and p27, and the stabilization of Rb expression. In addition, the suppression of the GSK3β/TSC2/mTOR pathway and deregulation of the GSK3β/β-catenin signaling were observed in cyproheptadine-treated UC cells. Furthermore, cyproheptadine-induced apoptosis was associated with ANGPTL4 expression followed by activation of caspase3 and PARP in UC cells. Our experimental results provide evidence that cyproheptadine is a suitable therapeutic agent for the treatment of UC.",
keywords = "ANGPTL4, Cyproheptadine, mTOR signaling, Urothelial carcinoma, Wnt/β-catenin signaling",
author = "Hsieh, {Hsiao Yen} and Shen, {Cheng Huang} and Lin, {Ru Inn} and Feng, {Yu Min} and Huang, {Shih Yuan} and Wang, {Yuan Hung} and Wu, {Shu Fen} and Hsu, {Cheng Da} and Chan, {Michael W Y}",
year = "2016",
month = "1",
day = "1",
doi = "10.1016/j.canlet.2015.09.018",
language = "English",
volume = "370",
pages = "56--65",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways

AU - Hsieh, Hsiao Yen

AU - Shen, Cheng Huang

AU - Lin, Ru Inn

AU - Feng, Yu Min

AU - Huang, Shih Yuan

AU - Wang, Yuan Hung

AU - Wu, Shu Fen

AU - Hsu, Cheng Da

AU - Chan, Michael W Y

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Cyproheptadine, a serotonin antagonist, has recently been reported to function as a novel therapeutic agent by inhibiting PI3K/AKT signaling in several human cancers. However, the therapeutic effect of cyproheptadine in urothelial carcinoma (UC) has never been explored. In this study, we determined the effect of cyproheptadine on the growth of five human UC cell lines and an in vivo xenograft model. The results showed that cyproheptadine exerted an inhibitory effect on the proliferation of UC cells both in vitro and in vivo. Cyproheptadine also induced cell cycle arrest in the G1 phase, subsequently followed by apoptosis and necrosis. The underlying mechanisms of cell cycle arrest were associated with the reduction of c-Myc, induction of p21 and p27, and the stabilization of Rb expression. In addition, the suppression of the GSK3β/TSC2/mTOR pathway and deregulation of the GSK3β/β-catenin signaling were observed in cyproheptadine-treated UC cells. Furthermore, cyproheptadine-induced apoptosis was associated with ANGPTL4 expression followed by activation of caspase3 and PARP in UC cells. Our experimental results provide evidence that cyproheptadine is a suitable therapeutic agent for the treatment of UC.

AB - Cyproheptadine, a serotonin antagonist, has recently been reported to function as a novel therapeutic agent by inhibiting PI3K/AKT signaling in several human cancers. However, the therapeutic effect of cyproheptadine in urothelial carcinoma (UC) has never been explored. In this study, we determined the effect of cyproheptadine on the growth of five human UC cell lines and an in vivo xenograft model. The results showed that cyproheptadine exerted an inhibitory effect on the proliferation of UC cells both in vitro and in vivo. Cyproheptadine also induced cell cycle arrest in the G1 phase, subsequently followed by apoptosis and necrosis. The underlying mechanisms of cell cycle arrest were associated with the reduction of c-Myc, induction of p21 and p27, and the stabilization of Rb expression. In addition, the suppression of the GSK3β/TSC2/mTOR pathway and deregulation of the GSK3β/β-catenin signaling were observed in cyproheptadine-treated UC cells. Furthermore, cyproheptadine-induced apoptosis was associated with ANGPTL4 expression followed by activation of caspase3 and PARP in UC cells. Our experimental results provide evidence that cyproheptadine is a suitable therapeutic agent for the treatment of UC.

KW - ANGPTL4

KW - Cyproheptadine

KW - mTOR signaling

KW - Urothelial carcinoma

KW - Wnt/β-catenin signaling

UR - http://www.scopus.com/inward/record.url?scp=84949456367&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949456367&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2015.09.018

DO - 10.1016/j.canlet.2015.09.018

M3 - Article

C2 - 26454215

AN - SCOPUS:84949456367

VL - 370

SP - 56

EP - 65

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

IS - 1

ER -