Journal
THERANOSTICS
Volume 10, Issue 17, Pages 7775-7786Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.46903
Keywords
Ferroptosis; glutaredoxin 5; cancer cells; gene silencing; free iron
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Funding
- National Research Foundation of Korea (NRF)
- Ministry of Science and ICT (MSIT), The Government of Korea [2019R1A2C2002259]
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Rationale: Loss of iron-sulfur cluster function predisposes cancer cells to ferroptosis by upregulating iron-starvation response, but the role of glutaredoxin 5 (GLRX5) silencing in ferroptosis remains unknown. We examined the role of GLRX5 functional loss in promoting ferroptosis in cisplatin-resistant head and neck cancer (HNC) cells. Methods: The effects of sulfasalazine treatment and GLRX5 gene silencing were tested on HNC cell lines and mouse tumor xenograft models. These effects were analyzed concerning cell viability and death, lipid reactive oxygen species (ROS) and mitochondrial iron production, labile iron pool, mRNA/protein expression, and malondialdehyde assays. Results: Cyst(e)ine deprivation, erastin, or sulfasalazine induced ferroptosis in HNC cells, which was relatively less sensitive in cisplatin-resistant HNC cells. Sulfasalazine or cyst(e)ine deprivation-induced ferroptosis resulted from increased lipid peroxidation and intracellular free iron, which were significantly promoted by short-interfering RNA or short hairpin RNA (shRNA) targeting GLRX5 ( P <0.05). GLRX5 silencing activated iron-starvation response and boosted up intracellular free iron through the iron-responsive element-binding activity of increased iron regulatory protein (increased transferrin receptor and decreased ferritin). These effects were rescued by resistant GLRX5 cDNA but not by catalytically inactive mutant GLRX5 K101Q. The same results were noted in an in vivo mouse model transplanted with vector or shGLRX5-transduced HNC cells and treated with sulfasalazine. Conclusion: Our data suggest that inhibition of GLRX5 predisposes therapy-resistant HNC cells to ferroptosis.
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