1 Citation (Scopus)

Abstract

Anticancer chemotherapeutic drugs mainly trigger apoptosis induction to eliminate malignant cells. However, many cancer cells are chemoresistant because of defective apoptosis induction. Targeting the autophagic pathway is currently regarded as an alternative strategy for cancer drug discovery. Penfluridol, an antipsychotic drug, has been reported to exert oncostatic effects, but the effect of penfluridol on lung cancer remains unknown. Herein, the antitumor activity of penfluridol was determined in vitro in non-small-cell lung cancer (NSCLC) cell lines using MTS, plate clonogenic, and transwell migration assays and in vivo in an orthotopic xenograft model. Flow cytometry, holotomographic microscopy, immunofluorescence, and immunohistochemistry were employed to determine the cell-death phenotype induced by penfluridol in vitro and in vivo. Western blotting and genetic knockdown by small interfering RNA were performed to explore the underlying mechanisms involved in penfluridol-mediated cell death. We uncovered that penfluridol inhibited the viability and motility of NSCLC cells in vitro and in vivo. Penfluridol induced nonapoptotic cell death by blocking autophagic flux and inducing accumulation of autophagosome-related protein, light chain 3 (LC3) B-II, in HCC827 and A549 NSCLC cells, and in an A549 orthotopic xenograft tumor model. Autophagosome accumulation-induced cell viability inhibition by penfluridol was mainly attributed to ATP energy deprivation. Moreover, we observed that patients with lung tumors expressing high LC3B had longer overall and disease-free survival times. Mechanistically, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways and activation of p38 mitogen-activated protein kinase (MAPK) were critical for penfluridol-induced autophagosome accumulation. Our findings identify that penfluridol acts as an inducer of ER stress and p38 MAPK activation, which led to UPR-mediated nonapoptotic cell death via autophagosome accumulation-caused energy loss. Penfluridol is clinically used for schizophrenia, and our study results strongly support penfluridol as a repurposed drug for treating NSCLC.

Original languageEnglish
Article number538
JournalCell Death and Disease
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 1 2019

Fingerprint

Penfluridol
Unfolded Protein Response
Lung Neoplasms
Cell Death
Adenosine Triphosphate
Non-Small Cell Lung Carcinoma
Endoplasmic Reticulum Stress
p38 Mitogen-Activated Protein Kinases
Heterografts
Autophagosomes
Neoplasms
Drug Repositioning
Apoptosis
Autophagy
Drug Discovery

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Autophagosome accumulation-mediated ATP energy deprivation induced by penfluridol triggers nonapoptotic cell death of lung cancer via activating unfolded protein response. / Hung, Wen Yueh; Chang, Jer Hwa; Cheng, Yu; Cheng, Guo Zhou; Huang, Hsiang Ching; Hsiao, Michael; Chung, Chi Li; Lee, Wei Jiunn; Chien, Ming Hsien.

In: Cell Death and Disease, Vol. 10, No. 8, 538, 01.08.2019.

Research output: Contribution to journalArticle

@article{47a30d910ceb465b8a969083ecbe2389,
title = "Autophagosome accumulation-mediated ATP energy deprivation induced by penfluridol triggers nonapoptotic cell death of lung cancer via activating unfolded protein response",
abstract = "Anticancer chemotherapeutic drugs mainly trigger apoptosis induction to eliminate malignant cells. However, many cancer cells are chemoresistant because of defective apoptosis induction. Targeting the autophagic pathway is currently regarded as an alternative strategy for cancer drug discovery. Penfluridol, an antipsychotic drug, has been reported to exert oncostatic effects, but the effect of penfluridol on lung cancer remains unknown. Herein, the antitumor activity of penfluridol was determined in vitro in non-small-cell lung cancer (NSCLC) cell lines using MTS, plate clonogenic, and transwell migration assays and in vivo in an orthotopic xenograft model. Flow cytometry, holotomographic microscopy, immunofluorescence, and immunohistochemistry were employed to determine the cell-death phenotype induced by penfluridol in vitro and in vivo. Western blotting and genetic knockdown by small interfering RNA were performed to explore the underlying mechanisms involved in penfluridol-mediated cell death. We uncovered that penfluridol inhibited the viability and motility of NSCLC cells in vitro and in vivo. Penfluridol induced nonapoptotic cell death by blocking autophagic flux and inducing accumulation of autophagosome-related protein, light chain 3 (LC3) B-II, in HCC827 and A549 NSCLC cells, and in an A549 orthotopic xenograft tumor model. Autophagosome accumulation-induced cell viability inhibition by penfluridol was mainly attributed to ATP energy deprivation. Moreover, we observed that patients with lung tumors expressing high LC3B had longer overall and disease-free survival times. Mechanistically, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways and activation of p38 mitogen-activated protein kinase (MAPK) were critical for penfluridol-induced autophagosome accumulation. Our findings identify that penfluridol acts as an inducer of ER stress and p38 MAPK activation, which led to UPR-mediated nonapoptotic cell death via autophagosome accumulation-caused energy loss. Penfluridol is clinically used for schizophrenia, and our study results strongly support penfluridol as a repurposed drug for treating NSCLC.",
author = "Hung, {Wen Yueh} and Chang, {Jer Hwa} and Yu Cheng and Cheng, {Guo Zhou} and Huang, {Hsiang Ching} and Michael Hsiao and Chung, {Chi Li} and Lee, {Wei Jiunn} and Chien, {Ming Hsien}",
year = "2019",
month = "8",
day = "1",
doi = "10.1038/s41419-019-1785-9",
language = "English",
volume = "10",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Autophagosome accumulation-mediated ATP energy deprivation induced by penfluridol triggers nonapoptotic cell death of lung cancer via activating unfolded protein response

AU - Hung, Wen Yueh

AU - Chang, Jer Hwa

AU - Cheng, Yu

AU - Cheng, Guo Zhou

AU - Huang, Hsiang Ching

AU - Hsiao, Michael

AU - Chung, Chi Li

AU - Lee, Wei Jiunn

AU - Chien, Ming Hsien

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Anticancer chemotherapeutic drugs mainly trigger apoptosis induction to eliminate malignant cells. However, many cancer cells are chemoresistant because of defective apoptosis induction. Targeting the autophagic pathway is currently regarded as an alternative strategy for cancer drug discovery. Penfluridol, an antipsychotic drug, has been reported to exert oncostatic effects, but the effect of penfluridol on lung cancer remains unknown. Herein, the antitumor activity of penfluridol was determined in vitro in non-small-cell lung cancer (NSCLC) cell lines using MTS, plate clonogenic, and transwell migration assays and in vivo in an orthotopic xenograft model. Flow cytometry, holotomographic microscopy, immunofluorescence, and immunohistochemistry were employed to determine the cell-death phenotype induced by penfluridol in vitro and in vivo. Western blotting and genetic knockdown by small interfering RNA were performed to explore the underlying mechanisms involved in penfluridol-mediated cell death. We uncovered that penfluridol inhibited the viability and motility of NSCLC cells in vitro and in vivo. Penfluridol induced nonapoptotic cell death by blocking autophagic flux and inducing accumulation of autophagosome-related protein, light chain 3 (LC3) B-II, in HCC827 and A549 NSCLC cells, and in an A549 orthotopic xenograft tumor model. Autophagosome accumulation-induced cell viability inhibition by penfluridol was mainly attributed to ATP energy deprivation. Moreover, we observed that patients with lung tumors expressing high LC3B had longer overall and disease-free survival times. Mechanistically, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways and activation of p38 mitogen-activated protein kinase (MAPK) were critical for penfluridol-induced autophagosome accumulation. Our findings identify that penfluridol acts as an inducer of ER stress and p38 MAPK activation, which led to UPR-mediated nonapoptotic cell death via autophagosome accumulation-caused energy loss. Penfluridol is clinically used for schizophrenia, and our study results strongly support penfluridol as a repurposed drug for treating NSCLC.

AB - Anticancer chemotherapeutic drugs mainly trigger apoptosis induction to eliminate malignant cells. However, many cancer cells are chemoresistant because of defective apoptosis induction. Targeting the autophagic pathway is currently regarded as an alternative strategy for cancer drug discovery. Penfluridol, an antipsychotic drug, has been reported to exert oncostatic effects, but the effect of penfluridol on lung cancer remains unknown. Herein, the antitumor activity of penfluridol was determined in vitro in non-small-cell lung cancer (NSCLC) cell lines using MTS, plate clonogenic, and transwell migration assays and in vivo in an orthotopic xenograft model. Flow cytometry, holotomographic microscopy, immunofluorescence, and immunohistochemistry were employed to determine the cell-death phenotype induced by penfluridol in vitro and in vivo. Western blotting and genetic knockdown by small interfering RNA were performed to explore the underlying mechanisms involved in penfluridol-mediated cell death. We uncovered that penfluridol inhibited the viability and motility of NSCLC cells in vitro and in vivo. Penfluridol induced nonapoptotic cell death by blocking autophagic flux and inducing accumulation of autophagosome-related protein, light chain 3 (LC3) B-II, in HCC827 and A549 NSCLC cells, and in an A549 orthotopic xenograft tumor model. Autophagosome accumulation-induced cell viability inhibition by penfluridol was mainly attributed to ATP energy deprivation. Moreover, we observed that patients with lung tumors expressing high LC3B had longer overall and disease-free survival times. Mechanistically, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways and activation of p38 mitogen-activated protein kinase (MAPK) were critical for penfluridol-induced autophagosome accumulation. Our findings identify that penfluridol acts as an inducer of ER stress and p38 MAPK activation, which led to UPR-mediated nonapoptotic cell death via autophagosome accumulation-caused energy loss. Penfluridol is clinically used for schizophrenia, and our study results strongly support penfluridol as a repurposed drug for treating NSCLC.

UR - http://www.scopus.com/inward/record.url?scp=85069487586&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069487586&partnerID=8YFLogxK

U2 - 10.1038/s41419-019-1785-9

DO - 10.1038/s41419-019-1785-9

M3 - Article

C2 - 31308361

AN - SCOPUS:85069487586

VL - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 8

M1 - 538

ER -