Ardisianone, a natural benzoquinone, efficiently induces apoptosis in human hormone-refractory prostate cancers through mitochondrial damage stress and survivin downregulation

Chia Chun Yu, Ping Jung Wu, Jui Ling Hsu, Yunn Fang Ho, Lih Ching Hsu, Yu Jia Chang, Hsun Shuo Chang, Ih Sheng Chen, Jih Hwa Guh

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

BACKGROUND Increasing evidence suggests that mitochondria play a central role in regulating cell apoptosis. Survivin, an inhibitor of apoptosis protein (IAP) family member, mediates resistance to cancer chemotherapy particularly in prostate cancers. Therefore, development of anticancer agents targeting mitochondria and survivin is a potential strategy. METHOD Cell proliferation was examined by sulforhodamine B, CFSE staining, and clonogenic assays. Mitochondrial membrane potential (δψm) and reactive oxygen species (ROS) were detected by flow cytometric analysis. Protein expression was detected by Western blot. RNA levels were examined by reverse transcription polymerase chain reaction assay. Overexpression of constitutively active Akt was also used in this study. RESULTS Ardisianone, a natural benzoquinone derivative, displayed anti-proliferative and apoptotic activities against human hormone-refractory prostate cancer cells (HRPC), PC-3, and DU-145. Ardisianone dramatically induced mitochondrial damage, identified by downregulation of Bcl-2 family proteins, ROS production, and loss of δψm. Ardisianone also inhibited Akt and mTOR/p70S6K pathways and induced a fast downregulation of survivin, leading to activation of mitochondria-involved caspase cascades. Overexpression of constitutively active Akt partly rescued ardisianone-mediated apoptotic signaling cascades. Furthermore, a long-term treatment of ardisianone caused an increase of endoplasmic reticulum (ER) stress, upregulation of cIAP1 and cIAP2, and apoptosis-inducing factor (AIF)-mediated caspase-independent apoptosis. CONCLUSIONS The data suggest that the ardisianone induces apoptosis in human prostate cancers through mitochondrial damage stress, leading to the inhibition of mTOR/p70S6K pathway, downregulation of Bcl-2 family members, degradation of survivin, and activation of caspase cascades. The data provide evidence supporting that ardisianone is a potential anticancer agent against HRPCs. Prostate 73: 133-145, 2013. © 2012 Wiley Periodicals, Inc.

Original languageEnglish
Pages (from-to)133-145
Number of pages13
JournalProstate
Volume73
Issue number2
DOIs
Publication statusPublished - Jan 2013

Fingerprint

Caspases
70-kDa Ribosomal Protein S6 Kinases
Prostatic Neoplasms
Mitochondria
Down-Regulation
Hormones
Apoptosis
lissamine rhodamine B
Antineoplastic Agents
Reactive Oxygen Species
Apoptosis Inducing Factor
Inhibitor of Apoptosis Proteins
Endoplasmic Reticulum Stress
Mitochondrial Membrane Potential
Human Activities
Reverse Transcription
Prostate
Proteins
Up-Regulation
Western Blotting

Keywords

  • AIF
  • ardisianone
  • ER stress
  • mitochondrial damage stress
  • survivin

ASJC Scopus subject areas

  • Urology
  • Oncology

Cite this

Ardisianone, a natural benzoquinone, efficiently induces apoptosis in human hormone-refractory prostate cancers through mitochondrial damage stress and survivin downregulation. / Yu, Chia Chun; Wu, Ping Jung; Hsu, Jui Ling; Ho, Yunn Fang; Hsu, Lih Ching; Chang, Yu Jia; Chang, Hsun Shuo; Chen, Ih Sheng; Guh, Jih Hwa.

In: Prostate, Vol. 73, No. 2, 01.2013, p. 133-145.

Research output: Contribution to journalArticle

Yu, Chia Chun ; Wu, Ping Jung ; Hsu, Jui Ling ; Ho, Yunn Fang ; Hsu, Lih Ching ; Chang, Yu Jia ; Chang, Hsun Shuo ; Chen, Ih Sheng ; Guh, Jih Hwa. / Ardisianone, a natural benzoquinone, efficiently induces apoptosis in human hormone-refractory prostate cancers through mitochondrial damage stress and survivin downregulation. In: Prostate. 2013 ; Vol. 73, No. 2. pp. 133-145.
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T1 - Ardisianone, a natural benzoquinone, efficiently induces apoptosis in human hormone-refractory prostate cancers through mitochondrial damage stress and survivin downregulation

AU - Yu, Chia Chun

AU - Wu, Ping Jung

AU - Hsu, Jui Ling

AU - Ho, Yunn Fang

AU - Hsu, Lih Ching

AU - Chang, Yu Jia

AU - Chang, Hsun Shuo

AU - Chen, Ih Sheng

AU - Guh, Jih Hwa

PY - 2013/1

Y1 - 2013/1

N2 - BACKGROUND Increasing evidence suggests that mitochondria play a central role in regulating cell apoptosis. Survivin, an inhibitor of apoptosis protein (IAP) family member, mediates resistance to cancer chemotherapy particularly in prostate cancers. Therefore, development of anticancer agents targeting mitochondria and survivin is a potential strategy. METHOD Cell proliferation was examined by sulforhodamine B, CFSE staining, and clonogenic assays. Mitochondrial membrane potential (δψm) and reactive oxygen species (ROS) were detected by flow cytometric analysis. Protein expression was detected by Western blot. RNA levels were examined by reverse transcription polymerase chain reaction assay. Overexpression of constitutively active Akt was also used in this study. RESULTS Ardisianone, a natural benzoquinone derivative, displayed anti-proliferative and apoptotic activities against human hormone-refractory prostate cancer cells (HRPC), PC-3, and DU-145. Ardisianone dramatically induced mitochondrial damage, identified by downregulation of Bcl-2 family proteins, ROS production, and loss of δψm. Ardisianone also inhibited Akt and mTOR/p70S6K pathways and induced a fast downregulation of survivin, leading to activation of mitochondria-involved caspase cascades. Overexpression of constitutively active Akt partly rescued ardisianone-mediated apoptotic signaling cascades. Furthermore, a long-term treatment of ardisianone caused an increase of endoplasmic reticulum (ER) stress, upregulation of cIAP1 and cIAP2, and apoptosis-inducing factor (AIF)-mediated caspase-independent apoptosis. CONCLUSIONS The data suggest that the ardisianone induces apoptosis in human prostate cancers through mitochondrial damage stress, leading to the inhibition of mTOR/p70S6K pathway, downregulation of Bcl-2 family members, degradation of survivin, and activation of caspase cascades. The data provide evidence supporting that ardisianone is a potential anticancer agent against HRPCs. Prostate 73: 133-145, 2013. © 2012 Wiley Periodicals, Inc.

AB - BACKGROUND Increasing evidence suggests that mitochondria play a central role in regulating cell apoptosis. Survivin, an inhibitor of apoptosis protein (IAP) family member, mediates resistance to cancer chemotherapy particularly in prostate cancers. Therefore, development of anticancer agents targeting mitochondria and survivin is a potential strategy. METHOD Cell proliferation was examined by sulforhodamine B, CFSE staining, and clonogenic assays. Mitochondrial membrane potential (δψm) and reactive oxygen species (ROS) were detected by flow cytometric analysis. Protein expression was detected by Western blot. RNA levels were examined by reverse transcription polymerase chain reaction assay. Overexpression of constitutively active Akt was also used in this study. RESULTS Ardisianone, a natural benzoquinone derivative, displayed anti-proliferative and apoptotic activities against human hormone-refractory prostate cancer cells (HRPC), PC-3, and DU-145. Ardisianone dramatically induced mitochondrial damage, identified by downregulation of Bcl-2 family proteins, ROS production, and loss of δψm. Ardisianone also inhibited Akt and mTOR/p70S6K pathways and induced a fast downregulation of survivin, leading to activation of mitochondria-involved caspase cascades. Overexpression of constitutively active Akt partly rescued ardisianone-mediated apoptotic signaling cascades. Furthermore, a long-term treatment of ardisianone caused an increase of endoplasmic reticulum (ER) stress, upregulation of cIAP1 and cIAP2, and apoptosis-inducing factor (AIF)-mediated caspase-independent apoptosis. CONCLUSIONS The data suggest that the ardisianone induces apoptosis in human prostate cancers through mitochondrial damage stress, leading to the inhibition of mTOR/p70S6K pathway, downregulation of Bcl-2 family members, degradation of survivin, and activation of caspase cascades. The data provide evidence supporting that ardisianone is a potential anticancer agent against HRPCs. Prostate 73: 133-145, 2013. © 2012 Wiley Periodicals, Inc.

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KW - mitochondrial damage stress

KW - survivin

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