The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells

Chang En Yang, Wen Ying Lee, Hung Wei Cheng, Chu Hung Chung, Fu Lowng Mi, Cheng Wei Lin

Research output: Contribution to journalArticle

Abstract

The major obstacle in current cancer therapy is the existence of cancer stem cells (CSCs), which are responsible for therapeutic resistance and contribute to metastasis and recurrence. Identification of reliable biomarkers for diagnostic and therapeutic targets is necessary for drug development and cancer treatment. In this study, we identified that the antipsychotic chlorpromazine (CPZ) exhibited potent anti-breast cancer and anti-CSC capabilities. Treatment with CPZ suppressed stemness properties including mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and stemness-related gene expressions in breast cancer cells and CSCs. Moreover, CPZ increased the susceptibility of breast cancer MCF7 cells and drug-resistant MCF7/ADR cells when combined with chemotherapies. Mechanistically, we identified that CPZ suppressed yes-associated protein (YAP) through modulating Hippo signaling and promoting proteasomal degradation of YAP. Elevated expression of YAP was confirmed to be crucial for stemness-related gene expressions, and was associated with invasiveness and stem-like signatures in breast cancer patients. Moreover, overexpression of YAP conferred poor outcomes particularly of basal-like breast cancer patients. Our data showed that YAP is a promising therapeutic target for breast CSCs, and CPZ has the potential to be a repurposed drug for breast cancer treatment.

Original languageEnglish
Pages (from-to)28-35
Number of pages8
JournalChemico-Biological Interactions
Volume302
DOIs
Publication statusPublished - Apr 1 2019

Fingerprint

Chlorpromazine
Drug Resistance
Antipsychotic Agents
Stem cells
Cells
Breast Neoplasms
Neoplastic Stem Cells
Oncology
Pharmaceutical Preparations
Proteins
Gene expression
MCF-7 Cells
Therapeutics
Aldehyde Dehydrogenase
Chemotherapy
Drug Repositioning
Biomarkers
Gene Expression
Degradation
Neoplasms

Keywords

  • Antipsychotic
  • Breast cancer
  • Cancer stem cells
  • YAP

ASJC Scopus subject areas

  • Toxicology

Cite this

The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells. / Yang, Chang En; Lee, Wen Ying; Cheng, Hung Wei; Chung, Chu Hung; Mi, Fu Lowng; Lin, Cheng Wei.

In: Chemico-Biological Interactions, Vol. 302, 01.04.2019, p. 28-35.

Research output: Contribution to journalArticle

Yang, Chang En ; Lee, Wen Ying ; Cheng, Hung Wei ; Chung, Chu Hung ; Mi, Fu Lowng ; Lin, Cheng Wei. / The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells. In: Chemico-Biological Interactions. 2019 ; Vol. 302. pp. 28-35.
@article{f41c2ab4c1b8447cab1243339970b9f0,
title = "The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells",
abstract = "The major obstacle in current cancer therapy is the existence of cancer stem cells (CSCs), which are responsible for therapeutic resistance and contribute to metastasis and recurrence. Identification of reliable biomarkers for diagnostic and therapeutic targets is necessary for drug development and cancer treatment. In this study, we identified that the antipsychotic chlorpromazine (CPZ) exhibited potent anti-breast cancer and anti-CSC capabilities. Treatment with CPZ suppressed stemness properties including mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and stemness-related gene expressions in breast cancer cells and CSCs. Moreover, CPZ increased the susceptibility of breast cancer MCF7 cells and drug-resistant MCF7/ADR cells when combined with chemotherapies. Mechanistically, we identified that CPZ suppressed yes-associated protein (YAP) through modulating Hippo signaling and promoting proteasomal degradation of YAP. Elevated expression of YAP was confirmed to be crucial for stemness-related gene expressions, and was associated with invasiveness and stem-like signatures in breast cancer patients. Moreover, overexpression of YAP conferred poor outcomes particularly of basal-like breast cancer patients. Our data showed that YAP is a promising therapeutic target for breast CSCs, and CPZ has the potential to be a repurposed drug for breast cancer treatment.",
keywords = "Antipsychotic, Breast cancer, Cancer stem cells, YAP",
author = "Yang, {Chang En} and Lee, {Wen Ying} and Cheng, {Hung Wei} and Chung, {Chu Hung} and Mi, {Fu Lowng} and Lin, {Cheng Wei}",
year = "2019",
month = "4",
day = "1",
doi = "10.1016/j.cbi.2019.01.033",
language = "English",
volume = "302",
pages = "28--35",
journal = "Chemico-Biological Interactions",
issn = "0009-2797",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells

AU - Yang, Chang En

AU - Lee, Wen Ying

AU - Cheng, Hung Wei

AU - Chung, Chu Hung

AU - Mi, Fu Lowng

AU - Lin, Cheng Wei

PY - 2019/4/1

Y1 - 2019/4/1

N2 - The major obstacle in current cancer therapy is the existence of cancer stem cells (CSCs), which are responsible for therapeutic resistance and contribute to metastasis and recurrence. Identification of reliable biomarkers for diagnostic and therapeutic targets is necessary for drug development and cancer treatment. In this study, we identified that the antipsychotic chlorpromazine (CPZ) exhibited potent anti-breast cancer and anti-CSC capabilities. Treatment with CPZ suppressed stemness properties including mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and stemness-related gene expressions in breast cancer cells and CSCs. Moreover, CPZ increased the susceptibility of breast cancer MCF7 cells and drug-resistant MCF7/ADR cells when combined with chemotherapies. Mechanistically, we identified that CPZ suppressed yes-associated protein (YAP) through modulating Hippo signaling and promoting proteasomal degradation of YAP. Elevated expression of YAP was confirmed to be crucial for stemness-related gene expressions, and was associated with invasiveness and stem-like signatures in breast cancer patients. Moreover, overexpression of YAP conferred poor outcomes particularly of basal-like breast cancer patients. Our data showed that YAP is a promising therapeutic target for breast CSCs, and CPZ has the potential to be a repurposed drug for breast cancer treatment.

AB - The major obstacle in current cancer therapy is the existence of cancer stem cells (CSCs), which are responsible for therapeutic resistance and contribute to metastasis and recurrence. Identification of reliable biomarkers for diagnostic and therapeutic targets is necessary for drug development and cancer treatment. In this study, we identified that the antipsychotic chlorpromazine (CPZ) exhibited potent anti-breast cancer and anti-CSC capabilities. Treatment with CPZ suppressed stemness properties including mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and stemness-related gene expressions in breast cancer cells and CSCs. Moreover, CPZ increased the susceptibility of breast cancer MCF7 cells and drug-resistant MCF7/ADR cells when combined with chemotherapies. Mechanistically, we identified that CPZ suppressed yes-associated protein (YAP) through modulating Hippo signaling and promoting proteasomal degradation of YAP. Elevated expression of YAP was confirmed to be crucial for stemness-related gene expressions, and was associated with invasiveness and stem-like signatures in breast cancer patients. Moreover, overexpression of YAP conferred poor outcomes particularly of basal-like breast cancer patients. Our data showed that YAP is a promising therapeutic target for breast CSCs, and CPZ has the potential to be a repurposed drug for breast cancer treatment.

KW - Antipsychotic

KW - Breast cancer

KW - Cancer stem cells

KW - YAP

UR - http://www.scopus.com/inward/record.url?scp=85060841957&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060841957&partnerID=8YFLogxK

U2 - 10.1016/j.cbi.2019.01.033

DO - 10.1016/j.cbi.2019.01.033

M3 - Article

AN - SCOPUS:85060841957

VL - 302

SP - 28

EP - 35

JO - Chemico-Biological Interactions

JF - Chemico-Biological Interactions

SN - 0009-2797

ER -