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Quercetin-induced apoptotic cascade in cancer cells: antioxidant versus estrogen receptor alpha-dependent mechanisms
Paola Galluzzo1, Chiara Martini, Pamela Bulzomi
1Department of Biology, University Roma Tre, Rome, Italy.
Abstract:
The flavonol quercetin, especially abundant in apple, wine, and onions, is reported to have anti-proliferative effects in many cancer cell lines. Antioxidant or pro-oxidant activities and kinase inhibition have been proposed as molecular mechanisms for these effects. In addition, an estrogenic activity has been observed but, at the present, it is poorly understood whether this latter activity plays a role in the quercetin-induced anti-proliferative effects. Here, we studied the molecular mechanisms of quercetin committed to the generation of an apoptotic cascade in cancer cells devoid or containing transfected estrogen receptor alpha (ERalpha; i.e., human cervix epitheloid carcinoma HeLa cells). Although none of tested quercetin concentrations increase reactive oxygen species (ROS) generation in HeLa cells, quercetin stimulation prevents the H(2)O(2)-induced ROS production both in the presence and in the absence of ERalpha. However, this flavonoid induces the activation of p38/MAPK, leading to the pro-apoptotic caspase-3 activation and to the poly(ADP-ribose) polymerase cleavage only in the presence of ERalpha. Notably, no down-regulation of survival kinases (i.e., AKT and ERK) was reported. Taken together, these findings suggest that quercetin results in HeLa cell death through an ERalpha-dependent mechanism involving caspase- and p38 kinase activation. These findings indicate new potential chemopreventive actions of flavonoids on cancer growth.
Insights
Quercetin, found in apples and onions, triggers cancer cell death via a mechanism dependent on estrogen receptor alpha (ERalpha). This involves activating specific protein pathways, suggesting potential cancer prevention strategies.
Area of Science:
- Cell Biology
- Molecular Oncology
- Natural Product Chemistry
Background:
- Quercetin, a plant flavonoid, exhibits anti-proliferative effects on various cancer cell lines.
- Proposed mechanisms include antioxidant/pro-oxidant activity and kinase inhibition.
- Quercetin's estrogenic activity's role in anti-cancer effects remains unclear.
Purpose of the Study:
- Investigate quercetin's molecular mechanisms in inducing apoptosis in cancer cells.
- Examine the role of estrogen receptor alpha (ERalpha) in quercetin's anti-cancer effects.
- Utilize human cervix epitheloid carcinoma HeLa cells, with and without transfected ERalpha.
Main Methods:
- Assessed reactive oxygen species (ROS) generation following quercetin treatment.
- Evaluated quercetin's effect on hydrogen peroxide (H2O2)-induced ROS production.
- Measured activation of p38/MAPK, caspase-3, and poly(ADP-ribose) polymerase (PARP) cleavage.
- Monitored levels of survival kinases AKT and ERK.
Main Results:
- Quercetin did not increase ROS generation in HeLa cells.
- Quercetin inhibited H2O2-induced ROS production irrespective of ERalpha presence.
- Quercetin activated p38/MAPK, leading to caspase-3 activation and PARP cleavage specifically in ERalpha-positive cells.
- Survival kinases AKT and ERK were not down-regulated.
Conclusions:
- Quercetin induces HeLa cell death through an ERalpha-dependent pathway.
- This mechanism involves the activation of caspase-3 and p38 kinase.
- Findings suggest potential chemopreventive roles for flavonoids in cancer treatment.
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