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Dihydrotestosterone enhances transforming growth factor-beta-induced apoptosis in hormone-sensitive prostate cancer
1Department of Surgery and Molecular Biology, Division of Urology, University of Maryland School of Medicine, Baltimore 21201, USA.
Abstract:
In this study, the potential interactions between dihydrotestosterone (DHT), a survival factor, and transforming growth factor-beta (TGF-beta), an apoptotic inducer, were examined in a derivative of the hormone-sensitive prostate cancer cell line LNCAP: The LNCaP TGF-beta receptor II cells, engineered to express TGF-beta receptor II, are sensitive to both DHT and TGF-beta. Surprisingly, when the LNCaP TGF-beta receptor II cells were treated with TGF-beta in the presence of physiological levels of DHT, both cell cycle arrest and apoptosis induction were significantly enhanced over TGF-beta alone. This effect temporally correlated with an increased expression of the cell cycle regulator p21 as well as the apoptotic executioner, procaspase-1, and a parallel down-regulation of the antiapoptotic protein, bcl-2. Expression of bax and caspase-3 proteins remained unchanged following treatment. Furthermore, apoptosis induction was suppressed by the caspase-1 inhibitor, z-YVAD, but not the caspase-3 inhibitor, z-DQMD, thus demonstrating the functional significance of increased procaspase-1 expression in TGF-beta-mediated apoptosis in prostate cancer cells. These results indicate that TGF-beta-mediated apoptosis can actually be enhanced by androgens through specific mechanisms involving cell cycle and apoptosis regulators and provide initial evidence on the ability of physiological levels of androgens to stimulate the intrinsic apoptotic potential of prostate cancer cells. Therefore, this study provides a molecular basis for the priming of prostate cancer cells for maximal apoptosis induction, during hormone- ablation therapy.
Insights
Dihydrotestosterone (DHT) enhances transforming growth factor-beta (TGF-beta)-induced apoptosis in prostate cancer cells. This interaction primes cancer cells for apoptosis during hormone therapy by upregulating cell cycle arrest and apoptotic proteins.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Androgens, like dihydrotestosterone (DHT), are crucial for prostate cancer cell survival.
- Transforming growth factor-beta (TGF-beta) is known to induce apoptosis in various cell types, including prostate cancer cells.
- The interplay between androgens and TGF-beta in prostate cancer apoptosis is not fully understood.
Purpose of the Study:
- To investigate the interaction between dihydrotestosterone (DHT) and transforming growth factor-beta (TGF-beta) in prostate cancer cells.
- To determine if DHT influences TGF-beta-mediated apoptosis.
- To elucidate the molecular mechanisms underlying any observed interactions.
Main Methods:
- Utilized a derivative of the hormone-sensitive prostate cancer cell line LNCaP, engineered to express TGF-beta receptor II (LNCaP TGF-beta receptor II cells).
- Treated cells with TGF-beta in the presence and absence of physiological levels of DHT.
- Assessed cell cycle arrest and apoptosis induction using molecular markers.
- Investigated the expression of key cell cycle and apoptosis regulators (p21, procaspase-1, bcl-2, bax, caspase-3).
- Utilized specific caspase inhibitors (z-YVAD for caspase-1, z-DQMD for caspase-3) to confirm the role of caspase-1.
Main Results:
- Physiological levels of DHT significantly enhanced TGF-beta-induced cell cycle arrest and apoptosis.
- This enhancement correlated with increased expression of p21 and procaspase-1, and decreased expression of bcl-2.
- Apoptosis induction was dependent on caspase-1 activity, as it was inhibited by z-YVAD but not z-DQMD.
- Expression of bax and caspase-3 remained unchanged.
Conclusions:
- Androgens, specifically DHT, can enhance TGF-beta-mediated apoptosis in prostate cancer cells.
- This potentiation involves specific molecular regulators of the cell cycle and apoptosis, including caspase-1.
- Physiological levels of androgens can stimulate the intrinsic apoptotic potential of prostate cancer cells.
- These findings provide a molecular basis for priming prostate cancer cells for maximal apoptosis induction during hormone ablation therapy.