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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation
1Department of Urology, Case Western Reserve University, Cleveland, OH 44106, USA.
Abstract:
Apigenin, a plant flavone, potentially activates wild-type p53 and induces apoptosis in cancer cells. We conducted detailed studies to understand its mechanism of action. Exposure of human prostate cancer 22Rv1 cells, harboring wild-type p53, to growth-suppressive concentrations (10-80 microM) of apigenin resulted in the stabilization of p53 by phosphorylation on critical serine sites, p14ARF-mediated downregulation of MDM2 protein, inhibition of NF-kappaB/p65 transcriptional activity, and induction of p21/WAF-1 in a dose- and time-dependent manner. Apigenin at these doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis. Interestingly, we observed accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after apigenin treatment. All these effects were significantly blocked by pretreatment of cells with the antioxidant N-acetylcysteine, p53 inhibitor pifithrin-alpha, and enzyme catalase. Apigenin-mediated p53 activation and apoptosis were further attenuated by p53 antisense oligonucleotide treatment. Exposure of cells to apigenin led to a decrease in the levels of Bcl-XL and Bcl-2 and increase in Bax, triggering caspase activation. Treatment with the caspase inhibitors Z-VAD-FMK and DEVD-CHO partially rescued these cells from apigenin-induced apoptosis. In vivo, apigenin administration demonstrated p53-mediated induction of apoptosis in 22Rv1 tumors. These results indicate that apigenin-induced apoptosis in 22Rv1 cells is initiated by a ROS-dependent disruption of the mitochondrial membrane potential through transcriptional-dependent and -independent p53 pathways.
Insights
Apigenin, a plant flavone, triggers apoptosis in prostate cancer cells by activating wild-type p53. This process involves reactive oxygen species generation and mitochondrial dysfunction, ultimately leading to programmed cell death.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Apigenin is a natural flavone with potential anticancer properties.
- The tumor suppressor protein p53 plays a crucial role in regulating cell growth and apoptosis.
- Understanding the precise mechanisms by which apigenin affects p53 and induces cancer cell death is essential.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying apigenin-induced apoptosis in human prostate cancer cells.
- To investigate the role of wild-type p53 activation in apigenin's anti-cancer effects.
- To determine the involvement of reactive oxygen species (ROS) and mitochondrial pathways in apigenin's action.
Main Methods:
- Treatment of human prostate cancer 22Rv1 cells with varying concentrations of apigenin.
- Analysis of p53 stabilization, phosphorylation, and mitochondrial translocation.
- Assessment of MDM2, p14ARF, NF-kappaB/p65, and p21/WAF-1 protein levels.
- Measurement of reactive oxygen species (ROS) generation, glutathione levels, and mitochondrial membrane potential.
- Evaluation of cytochrome c release, Bcl-2 family protein expression, and caspase activation.
- In vivo studies using 22Rv1 tumor models in mice.
Main Results:
- Apigenin induced p53 stabilization via phosphorylation and downregulated MDM2, leading to p21/WAF-1 induction.
- Apigenin triggered ROS generation, glutathione depletion, mitochondrial membrane potential disruption, and cytochrome c release.
- p53 accumulated in mitochondria, and apoptosis was blocked by antioxidants and p53 inhibitors.
- Apigenin altered Bcl-2 family proteins, activating caspases and inducing apoptosis.
- In vivo administration of apigenin demonstrated p53-mediated apoptosis in prostate tumors.
Conclusions:
- Apigenin induces apoptosis in prostate cancer cells through a ROS-dependent mechanism.
- The process involves disruption of mitochondrial membrane potential and activation of both p53-dependent and independent pathways.
- Apigenin's ability to activate p53 and induce apoptosis suggests its potential as an anticancer therapeutic agent.
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