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Resveratrol inhibits cancer cell proliferation by impairing oxidative phosphorylation and inducing oxidative stress
Sara Rodríguez-Enríquez1, Silvia Cecilia Pacheco-Velázquez1, Álvaro Marín-Hernández1
1Departamento de Bioquímica, Instituto Nacional de Cardiología, Mexico.
Abstract:
The resveratrol (RSV) efficacy to affect the proliferation of several cancer cell lines was initially examined. RSV showed higher potency to decrease growth of metastatic HeLa and MDA-MB-231 (IC50 = 200-250 μM) cells than of low metastatic MCF-7, SiHa and A549 (IC50 = 400-500 μM) and non-cancer HUVEC and 3T3 (IC50≥600 μM) cells after 48 h exposure. In order to elucidate the biochemical mechanisms underlying RSV anti-cancer effects, the energy metabolic pathways and the oxidative stress metabolism were analyzed in HeLa cells as metastatic-type cell model. RSV (200 μM/48 h) significantly decreased both glycolysis and oxidative phosphorylation (OxPhos) protein contents (30-90%) and fluxes (40-70%) vs. non-treated cells. RSV (100 μM/1-5 min) also decreased at a greater extent OxPhos flux (net ADP-stimulated respiration) of isolated tumor mitochondria (> 50%) than of non-tumor mitochondria (< 50%), particularly with succinate as oxidizable substrate. In addition, RSV promoted an excessive cellular ROS (2-3 times) production corresponding with a significant decrement in the SOD activity (but not in its content) and GSH levels; whereas the catalase, glutahione reductase, glutathione peroxidase and glutathione-S-transferase activities (but not their contents) remained unchanged. RSV (200 μM/48 h) also induced cellular death although not by apoptosis but rather by promoting a strong mitophagy activation (65%). In conclusion, RSV impaired OxPhos by inducing mitophagy and ROS over-production, which in turn halted metastatic HeLa cancer cell growth.
Insights
Resveratrol (RSV) effectively inhibits metastatic cancer cell growth by disrupting energy metabolism and increasing oxidative stress. This natural compound triggers mitophagy, leading to cell death without apoptosis, highlighting its anti-cancer potential.
Area of Science:
- Biochemistry
- Cell Biology
- Cancer Research
- Metabolomics
Background:
- Resveratrol (RSV) is a natural polyphenol with demonstrated anti-cancer properties.
- Understanding the precise molecular mechanisms of RSV's anti-proliferative effects is crucial for therapeutic development.
- Metabolic reprogramming and oxidative stress are key hallmarks of cancer progression.
Purpose of the Study:
- To evaluate the efficacy of resveratrol (RSV) in inhibiting the proliferation of various cancer cell lines.
- To elucidate the underlying biochemical mechanisms of RSV's anti-cancer effects, focusing on energy metabolism and oxidative stress in metastatic HeLa cells.
- To investigate the role of mitophagy and reactive oxygen species (ROS) in RSV-induced cancer cell death.
Main Methods:
- Assessed RSV's dose-dependent efficacy (IC50) on the proliferation of metastatic (HeLa, MDA-MB-231) and non-metastatic (MCF-7, SiHa, A549) cancer cells, alongside non-cancerous cells (HUVEC, 3T3).
- Analyzed energy metabolic pathways (glycolysis, oxidative phosphorylation) and oxidative stress markers in HeLa cells treated with RSV.
- Measured mitochondrial respiration, cellular ROS production, antioxidant enzyme activities (SOD, catalase, etc.), and glutathione (GSH) levels.
- Determined the mode of cell death induced by RSV, specifically investigating apoptosis and mitophagy.
Main Results:
- RSV significantly reduced the proliferation of metastatic cancer cells (HeLa, MDA-MB-231) at lower concentrations (IC50: 200-250 μM) compared to less metastatic cells (IC50: 400-500 μM) and non-cancer cells (IC50 ≥ 600 μM) after 48h exposure.
- In HeLa cells, RSV (200 μM/48h) markedly decreased glycolysis and oxidative phosphorylation (OxPhos) protein content (30-90%) and fluxes (40-70%).
- RSV (100 μM/1-5min) significantly inhibited OxPhos flux in isolated tumor mitochondria (>50%) more than in non-tumor mitochondria (<50%), particularly with succinate.
- RSV treatment led to a 2-3 fold increase in cellular ROS production, accompanied by decreased SOD activity and GSH levels, while other antioxidant enzymes remained unaffected.
- RSV induced cell death primarily through mitophagy activation (65%), not apoptosis.
Conclusions:
- Resveratrol exhibits potent anti-proliferative effects against metastatic cancer cells by targeting fundamental metabolic pathways.
- RSV impairs oxidative phosphorylation (OxPhos) and induces excessive ROS production, contributing to its anti-cancer activity.
- Mitophagy activation is a key mechanism by which RSV promotes cancer cell death, offering a novel therapeutic strategy.
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