Abstract
Background and purpose:
Cancer cells exhibit more dependence on iron and enhanced sensitivity to ferroptosis than normal cells. Quercetin is known to possess anti-cancer effects, but the molecular mechanism is largely unknown. In this study, we aimed to investigate the involvement of lysosome function and ferroptosis to further explore the anti-cancer potential of Quercetin.
Experimental approaches:
We utilized MTT assay and DNA content analysis to evaluate the cytotoxicity; colony formation assay to investigate cell proliferation; flow cytometry and confocal microscopy to detect lysosomal acidification and protease enzyme activity; Western blotting, cell subfraction, RT-PCR and siRNA transfection were used to establish molecular mechanisms of action.
Key results:
Quercetin is able to promote p53-independent cell death in various cancer cell lines. Although Quercetin induces autophagy, genetic silencing of Atg7 fails to affect Quercetin-induced cell death. In contrast, both lysosome inhibitors and TFEB knockdown can prevent Quercetin-induced cell death, suggesting the involvement of lysosome. Next, Quercetin is found to induce lysosomal activation sequentially through TFEB nuclear translocation and transcriptional activation of lysosomal genes. Notably, Quercetin promotes lysosome-dependent ferritin degradation and free iron release. This action and Quercetin-induced ROS generation synergistically result in lipid peroxidation and ferroptosis. Furthermore, we provided evidence that Bid may link ferroptosis with apoptosis to cause cell death.
Conclusion and implications:
In summary, our study demonstrates that Quercetin induces TFEB-mediated lysosome activation and then promotes ferritin degradation, which consequently leads to ferroptosis and Bid-involved apoptosis. Results from this study may expand our current knowledge about the mechanism of Quercetin in anti-cancer therapy.
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