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Underlying mechanism of quercetin-induced cell death in human glioma cells
Eui Joong Kim1, Chang Hwa Choi, Ji Yeon Park
1Department of Neurosurgery, College of Medicine, Pusan National University, Pusan 602-739, South Korea.
Abstract:
There has been considerable interest in recent years in the anti-tumor activities of flavonoids. Quercetin, a ubiquitous bioactive flavonoid, can inhibit proliferation and induce apoptosis in a variety of cancer cells. However, the precise molecular mechanism by which quercetin induces apoptosis in cancer cells is poorly understood. The present study was undertaken to examine the effect of quercetin on cell viability and to determine its underlying mechanism in human glioma cells. Quercetin resulted in loss of cell viability in a dose- and time-dependent manner and the decrease in cell viability was mainly attributed to cell death. Quercetin did not increase reactive oxygen species (ROS) generation and the quercetin-induced cell death was also not affected by antioxidants, suggesting that ROS generation is not involved in loss of cell viability. Western blot analysis showed that quercetin treatment caused rapid reduction in phosphorylation of extracellular signal-regulated kinase (ERK) and Akt. Transient transfection with constitutively active forms of MEK and Akt protected against the quercetin-induced loss of cell viability. Quercetin-induced depolarization of mitochondrial membrane potential. Caspase activity was stimulated by quercetin and caspase inhibitors prevented the quercetin-induced loss of cell viability. Quercetin resulted in a decrease in expression of survivin, antiapoptotic proteins. Taken together, these findings suggest that quercetin results in human glioma cell death through caspase-dependent mechanisms involving down-regulation of ERK, Akt, and survivin.
Insights
Quercetin induces human glioma cell death by activating caspases and down-regulating survival proteins, independent of reactive oxygen species. This flavonoid inhibits extracellular signal-regulated kinase (ERK) and Akt pathways, leading to apoptosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Flavonoids, like quercetin, show anti-tumor potential.
- Quercetin inhibits cancer cell proliferation and induces apoptosis.
- The precise molecular mechanisms of quercetin-induced apoptosis in cancer remain unclear.
Purpose of the Study:
- Investigate quercetin's effect on human glioma cell viability.
- Elucidate the underlying molecular mechanisms of quercetin-induced apoptosis in glioma cells.
Main Methods:
- Assessed cell viability and cell death.
- Measured reactive oxygen species (ROS) generation.
- Analyzed extracellular signal-regulated kinase (ERK) and Akt phosphorylation via Western blot.
- Investigated mitochondrial membrane potential.
- Assayed caspase activity.
- Examined survivin expression.
Main Results:
- Quercetin decreased glioma cell viability dose- and time-dependently, primarily via cell death.
- ROS generation was not involved; antioxidants did not affect quercetin-induced cell death.
- Quercetin reduced ERK and Akt phosphorylation; active MEK and Akt partially protected cells.
- Mitochondrial membrane potential was disrupted.
- Caspase activity increased, and inhibitors blocked cell death.
- Quercetin decreased antiapoptotic survivin expression.
Conclusions:
- Quercetin induces human glioma cell death through a caspase-dependent pathway.
- This process involves the down-regulation of ERK, Akt, and survivin.
- ROS generation is not implicated in quercetin-mediated glioma cell death.