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


METHODS
Cell proliferation was examined by sulforhodamine B, CFSE staining, and clonogenic assays. Mitochondrial membrane potential (ΔΨ(m) ) 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 ΔΨ(m) . 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.
School of Pharmacy, National Taiwan University, Taipei, Taiwan.
Chia-Chun
CC
Yu
Ping-Jung
PJ
Wu
Jui-Ling
JL
Hsu
Yunn-Fang
YF
Ho
Lih-Ching
LC
Hsu
Yu-Jia
YJ
Chang
Hsun-Shuo
HS
Chang
Ih-Sheng
IS
Chen
Jih-Hwa
JH
Guh
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077022:Survivin
C107489:BIRC5 protein, human; D016227:Benzoquinones; D051034:Inhibitor of Apoptosis Proteins; D017382:Reactive Oxygen Species; D000077022:Survivin; C080919:ardisianone A