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Molecular targets for green tea in prostate cancer prevention
Vaqar M Adhami1, Nihal Ahmad, Hasan Mukhtar
1Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
Abstract:
Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer-related deaths in American males. For these reasons, it is necessary to intensify our efforts for better understanding and development of novel treatment and chemopreventive approaches for this disease. In recent years, green tea has gained considerable attention as an agent that could reduce the risk of several cancer types. The cancer-chemopreventive effects of green tea appear to be mediated by the polyphenolic constituents present therein. Based on geographical observations that suggest that the incidence of PCa is lower in Japanese and Chinese populations that consume green tea on a regular basis, we hypothesized that green tea and/or its constituents could be effective for chemoprevention of PCa. To investigate this hypothesis, we initiated a program for the chemoprevention of PCa by green tea. In cell-culture systems that employ human PCa cells DU145 (androgen insensitive) and LNCaP (androgen sensitive), we found that the major polyphenolic constituent (-)-epigallocatechin-3-gallate (EGCG) of green tea induces 1) apoptosis, 2) cell-growth inhibition, and 3) cyclin kinase inhibitor WAF-1/p21-mediated cell-cycle dysregulation. More recently, using a cDNA microarray, we found that EGCG treatment of LNCaP cells results in 1) induction of genes that functionally exhibit growth-inhibitory effects, and 2) repression of genes that belong to the G-protein signaling network. In animal studies that employ a transgenic adenocarcinoma of the mouse prostate (TRAMP), which is a model that mimics progressive forms of human prostatic disease, we observed that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to 6 cups of green tea/d) significantly inhibits PCa development and metastasis. We extended these studies and more recently observed increased expression of genes related to angiogenesis such as vascular endothelial growth factor (VEGF) and those related to metastasis such as matrix metalloproteinases (MMP)-2 and MMP-9 in prostate cancer of TRAMP mice. Oral feeding of GTP as the sole source of drinking fluid to TRAMP mice results in significant inhibition of VEGF, MMP-2 and MMP-9. These data suggest that there are multiple targets for PCa chemoprevention by green tea and highlight the need for further studies to identify novel pathways that may be modulated by green tea or its polyphenolic constituents that could be further exploited for prevention and/or treatment of PCa.
Insights
Green tea polyphenols, particularly EGCG, show promise in preventing prostate cancer (PCa). Studies indicate EGCG induces apoptosis and inhibits cell growth, while green tea polyphenols (GTP) reduce PCa development and metastasis in mouse models.
Area of Science:
- Oncology
- Chemoprevention
- Molecular Biology
Background:
- Prostate cancer (PCa) is a leading cause of cancer-related deaths in American males.
- Geographical data suggests green tea consumption correlates with lower PCa incidence.
- Green tea's chemopreventive effects are attributed to its polyphenolic constituents.
Purpose of the Study:
- To investigate the potential of green tea and its constituents for PCa chemoprevention.
- To elucidate the molecular mechanisms underlying green tea's anti-cancer effects in PCa.
Main Methods:
- In vitro studies using human PCa cell lines (DU145 and LNCaP) treated with (-)-epigallocatechin-3-gallate (EGCG).
- cDNA microarray analysis to identify gene expression changes in EGCG-treated LNCaP cells.
- In vivo studies using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model with oral administration of green tea polyphenols (GTP).
Main Results:
- EGCG induced apoptosis, inhibited cell growth, and dysregulated the cell cycle via WAF-1/p21 in human PCa cells.
- EGCG modulated gene expression in LNCaP cells, inducing growth-inhibitory genes and repressing G-protein signaling genes.
- Oral GTP administration significantly inhibited PCa development, metastasis, and expression of angiogenesis (VEGF) and metastasis (MMP-2, MMP-9) genes in TRAMP mice.
Conclusions:
- Green tea polyphenols, especially EGCG, exhibit significant chemopreventive effects against PCa.
- Green tea targets multiple pathways involved in PCa development, including cell growth, cell cycle, angiogenesis, and metastasis.
- Further research into green tea's molecular targets could lead to novel PCa prevention and treatment strategies.