Back to Search
Start Over
Mechanisms of dihydrotestosterone action on resveratrol-induced anti-proliferation in breast cancer cells with different ERα status
- Source :
- Oncotarget
- Publication Year :
- 2015
- Publisher :
- Impact Journals, LLC, 2015.
-
Abstract
- Dihydrotestosterone (DHT) has been shown to promote breast cancer growth via different mechanisms. In addition to binding to ERα, the DHT membrane receptor exists on integrin αvβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin αvβ3. Resveratrol and DHT signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, whereas resveratrol is pro-apoptotic. In this study, we examined the mechanism by which DHT inhibits resveratrol-induced apoptosis in human ERα 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 ERα 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.
- Subjects :
- endocrine system
medicine.medical_specialty
DHT
Apoptosis
Breast Neoplasms
resveratrol
Resveratrol
Biology
urologic and male genital diseases
chemistry.chemical_compound
breast cancer
estrogen receptor-α
Cell Line, Tumor
Internal medicine
Stilbenes
polycyclic compounds
medicine
Humans
Drug Interactions
Phosphorylation
skin and connective tissue diseases
Receptor
Cell Proliferation
Cell growth
integrin αvβ3
Estrogen Receptor alpha
Dihydrotestosterone
Integrin alphaVbeta3
Cell biology
Endocrinology
Oncology
chemistry
Cancer cell
MCF-7 Cells
Female
Signal transduction
Estrogen receptor alpha
hormones, hormone substitutes, and hormone antagonists
Research Paper
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....560d498f8e60bde42e5d027ccb22489f