Mechanisms of dihydrotestosterone action on resveratrolinduced anti-proliferation in breast cancer cells with different ER status

Yu Tang Chin, Sheng Huei Yang, Tung Cheng Chang, Chun A. Changou, Hsuan Yu Lai, Earl Fu, Wei Chun HuangFu, Paul J. Davis, Hung Yun Lin, Leroy F. Liu

研究成果: 雜誌貢獻文章

23 引文 (Scopus)

摘要

Dihydrotestosterone (DHT) has been shown to promote breast cancer growth via different mechanisms. In addition to binding to ERa, the DHT membrane receptor exists on integrin avβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin avβ3. Resveratrol and DHT signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, whereas resveratrol is proapoptotic. In this study, we examined the mechanism by which DHT inhibits resveratrolinduced apoptosis in human ERa positive (MCF-7) and negative (MDA-MB-231) breast cancer cells. DHT inhibited resveratrol-stimulated phosphorylation of Ser-15 of p53 in a concentration-dependent manner. These effects of DHT on resveratrol action were blocked by an ERa antagonist, ICI 182,780, in MCF-7 breast cancer cells. DHT inhibited resveratrol-induced nuclear complex of p53-COX-2 formation which is required p53- dependent apoptosis. ChIP studies of COX-2/p53 binding to DNA and expression of p53-responsive genes indicated that DHT inhibited resveratrol-induced p53-directed transcriptional activity. In addition, DHT did inhibit resveratrol-induced COX-2/p53- dependent gene expression. These results suggest that DHT inhibits p53-dependent apoptosis in breast cancer cells by interfering with nuclear COX-2 accumulation which is essential for stimulation of apoptotic pathways. Thus, the surface receptor sites for resveratrol and DHT are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive. These studies provide new insights into the antagonizing effects of resveratrol versus DHT, an important step toward better understanding and eventually treating breast cancer. It also indicates the complex pathways by which apoptosis is induced by resveratrol in DHT-depleted and -repleted environments.
原文英語
頁(從 - 到)35866-35879
頁數14
期刊Oncotarget
6
發行號34
DOIs
出版狀態已發佈 - 2015

指紋

Dihydrotestosterone
Breast Neoplasms
Apoptosis
p53 Genes
Integrins
resveratrol
Androgen Receptors

ASJC Scopus subject areas

  • Oncology

引用此文

Mechanisms of dihydrotestosterone action on resveratrolinduced anti-proliferation in breast cancer cells with different ER status. / Chin, Yu Tang; Yang, Sheng Huei; Chang, Tung Cheng; Changou, Chun A.; Lai, Hsuan Yu; Fu, Earl; HuangFu, Wei Chun; Davis, Paul J.; Lin, Hung Yun; Liu, Leroy F.

於: Oncotarget, 卷 6, 編號 34, 2015, p. 35866-35879.

研究成果: 雜誌貢獻文章

Chin, Yu Tang ; Yang, Sheng Huei ; Chang, Tung Cheng ; Changou, Chun A. ; Lai, Hsuan Yu ; Fu, Earl ; HuangFu, Wei Chun ; Davis, Paul J. ; Lin, Hung Yun ; Liu, Leroy F. / Mechanisms of dihydrotestosterone action on resveratrolinduced anti-proliferation in breast cancer cells with different ER status. 於: Oncotarget. 2015 ; 卷 6, 編號 34. 頁 35866-35879.
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abstract = "Dihydrotestosterone (DHT) has been shown to promote breast cancer growth via different mechanisms. In addition to binding to ERa, the DHT membrane receptor exists on integrin avβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin avβ3. Resveratrol and DHT signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, whereas resveratrol is proapoptotic. In this study, we examined the mechanism by which DHT inhibits resveratrolinduced apoptosis in human ERa positive (MCF-7) and negative (MDA-MB-231) breast cancer cells. DHT inhibited resveratrol-stimulated phosphorylation of Ser-15 of p53 in a concentration-dependent manner. These effects of DHT on resveratrol action were blocked by an ERa antagonist, ICI 182,780, in MCF-7 breast cancer cells. DHT inhibited resveratrol-induced nuclear complex of p53-COX-2 formation which is required p53- dependent apoptosis. ChIP studies of COX-2/p53 binding to DNA and expression of p53-responsive genes indicated that DHT inhibited resveratrol-induced p53-directed transcriptional activity. In addition, DHT did inhibit resveratrol-induced COX-2/p53- dependent gene expression. These results suggest that DHT inhibits p53-dependent apoptosis in breast cancer cells by interfering with nuclear COX-2 accumulation which is essential for stimulation of apoptotic pathways. Thus, the surface receptor sites for resveratrol and DHT are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive. These studies provide new insights into the antagonizing effects of resveratrol versus DHT, an important step toward better understanding and eventually treating breast cancer. It also indicates the complex pathways by which apoptosis is induced by resveratrol in DHT-depleted and -repleted environments.",
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AU - Chin, Yu Tang

AU - Yang, Sheng Huei

AU - Chang, Tung Cheng

AU - Changou, Chun A.

AU - Lai, Hsuan Yu

AU - Fu, Earl

AU - HuangFu, Wei Chun

AU - Davis, Paul J.

AU - Lin, Hung Yun

AU - Liu, Leroy F.

PY - 2015

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N2 - Dihydrotestosterone (DHT) has been shown to promote breast cancer growth via different mechanisms. In addition to binding to ERa, the DHT membrane receptor exists on integrin avβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin avβ3. Resveratrol and DHT signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, whereas resveratrol is proapoptotic. In this study, we examined the mechanism by which DHT inhibits resveratrolinduced apoptosis in human ERa positive (MCF-7) and negative (MDA-MB-231) breast cancer cells. DHT inhibited resveratrol-stimulated phosphorylation of Ser-15 of p53 in a concentration-dependent manner. These effects of DHT on resveratrol action were blocked by an ERa antagonist, ICI 182,780, in MCF-7 breast cancer cells. DHT inhibited resveratrol-induced nuclear complex of p53-COX-2 formation which is required p53- dependent apoptosis. ChIP studies of COX-2/p53 binding to DNA and expression of p53-responsive genes indicated that DHT inhibited resveratrol-induced p53-directed transcriptional activity. In addition, DHT did inhibit resveratrol-induced COX-2/p53- dependent gene expression. These results suggest that DHT inhibits p53-dependent apoptosis in breast cancer cells by interfering with nuclear COX-2 accumulation which is essential for stimulation of apoptotic pathways. Thus, the surface receptor sites for resveratrol and DHT are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive. These studies provide new insights into the antagonizing effects of resveratrol versus DHT, an important step toward better understanding and eventually treating breast cancer. It also indicates the complex pathways by which apoptosis is induced by resveratrol in DHT-depleted and -repleted environments.

AB - Dihydrotestosterone (DHT) has been shown to promote breast cancer growth via different mechanisms. In addition to binding to ERa, the DHT membrane receptor exists on integrin avβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin avβ3. Resveratrol and DHT signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, whereas resveratrol is proapoptotic. In this study, we examined the mechanism by which DHT inhibits resveratrolinduced apoptosis in human ERa positive (MCF-7) and negative (MDA-MB-231) breast cancer cells. DHT inhibited resveratrol-stimulated phosphorylation of Ser-15 of p53 in a concentration-dependent manner. These effects of DHT on resveratrol action were blocked by an ERa antagonist, ICI 182,780, in MCF-7 breast cancer cells. DHT inhibited resveratrol-induced nuclear complex of p53-COX-2 formation which is required p53- dependent apoptosis. ChIP studies of COX-2/p53 binding to DNA and expression of p53-responsive genes indicated that DHT inhibited resveratrol-induced p53-directed transcriptional activity. In addition, DHT did inhibit resveratrol-induced COX-2/p53- dependent gene expression. These results suggest that DHT inhibits p53-dependent apoptosis in breast cancer cells by interfering with nuclear COX-2 accumulation which is essential for stimulation of apoptotic pathways. Thus, the surface receptor sites for resveratrol and DHT are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive. These studies provide new insights into the antagonizing effects of resveratrol versus DHT, an important step toward better understanding and eventually treating breast cancer. It also indicates the complex pathways by which apoptosis is induced by resveratrol in DHT-depleted and -repleted environments.

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