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Melatonin Induces Apoptotic Cell Death via p53 in LNCaP Cells
1Department of Biomedical Engineering, College of Health Science, Yonsei University, Wonju 220-710, Korea.
Abstract:
In this study, we examined whether melatonin promotes apoptotic cell death via p53 in prostate LNCaP cells. Melatonin treatment significantly curtailed the growth of LNCaP cells in a dose- and time-dependent manner. Melatonin treatment (0 to 3 mM) induced the fragmentation of poly(ADP-ribose) polymerase (PARP) and activation of caspase-3, caspase-8, and caspase-9. Moreover, melatonin markedly activated Bax expression and decreased Bcl-2 expression in dose increments. To investigate p53 and p21 expression, LNCaP cells were treated with 0 to 3 mM melatonin. Melatonin increased the expressions of p53, p21, and p27. Treatment with mitogen-activated protein kinase (MAPK) inhibitors, PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB202190 (p38 inhibitor), confirmed that the melatonin-induced apoptosis was p21-dependent, but ERK-independent. With the co-treatment of PD98059 and melatonin, the expression of p-p53, p21, and MDM2 did not decrease. These effects were opposite to the expression of p-p53, p21, and MDM2 observed with SP600125 and SB202190 treatments. Together, these results suggest that p53-dependent induction of JNK/p38 MAPK directly participates in apoptosis induced by melatonin.
Insights
Melatonin induces programmed cell death in prostate cancer cells by activating p53 and related pathways. This study reveals melatonin
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Prostate cancer remains a significant health concern.
- Melatonin's role in cancer apoptosis is under investigation.
- The p53 pathway is crucial in regulating cell death.
Purpose of the Study:
- To investigate the mechanism of melatonin-induced apoptosis in prostate cancer LNCaP cells.
- To determine the involvement of the p53 pathway and mitogen-activated protein kinases (MAPKs) in this process.
Main Methods:
- LNCaP cells were treated with varying concentrations of melatonin.
- Apoptosis markers such as PARP fragmentation and caspase activation were assessed.
- Expression levels of key proteins including p53, p21, Bax, Bcl-2, and MDM2 were analyzed.
- The role of MAPK pathways (ERK, JNK, p38) was evaluated using specific inhibitors.
Main Results:
- Melatonin significantly inhibited LNCaP cell growth in a dose- and time-dependent manner.
- Melatonin induced apoptosis, evidenced by PARP cleavage and caspase activation.
- Melatonin upregulated pro-apoptotic Bax and downregulated anti-apoptotic Bcl-2.
- Melatonin increased the expression of p53, p21, and p27.
- Melatonin-induced apoptosis was dependent on p21 and JNK/p38 MAPK, but not ERK.
- Inhibitor studies indicated p53-dependent JNK/p38 MAPK activation in melatonin-induced apoptosis.
Conclusions:
- Melatonin effectively induces apoptosis in prostate cancer cells.
- The p53 pathway, p21, and JNK/p38 MAPK signaling are critical mediators of melatonin's anti-cancer effects.
- These findings suggest melatonin as a potential therapeutic agent for prostate cancer.
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