Plumbagin reduction by thioredoxin reductase 1 possesses synergy effects with GLUT1 inhibitor on KEAP1-mutant NSCLC cells - 16/01/22
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Abstract |
Thioredoxin reductase 1 (TrxR1 or TXNRD1) is a major enzyme in cellular redox regulation and is considered as a drug target for cancer therapy. Previous studies have reported that plumbagin caused reactive oxygen species (ROS)-dependent apoptosis via inhibiting TrxR1 activity or being reduced by TrxR1, leading to selectively cancer cell death. However, the mechanism of TrxR1-mediated redox cycling of plumbagin is obscure and the evidence for plumbagin targeting TrxR1 is still lacking. Herein, we demonstrated that TrxR1 catalyzed plumbagin reduction in both selenocysteine (Sec)-dependent and independent manners, and its activity relied on the intact N-terminal motif of TrxR1, but a high-efficiency reduction was supported by the C-terminal thiols. During the redox cycling of plumbagin, excessive ROS production was observed coupled with oxygen. Using LC-MS and TrxR1 mutants, we found that the Sec residue of TrxR1 was modified by plumbagin, which converted the enzyme from antioxidant to pro-oxidant. Furthermore, we evaluated the therapeutic potential of plumbagin in non-small cell lung cancer (NSCLC), and found that Kelch-like ECH-associated protein 1 (KEAP1)-mutant NSCLC cells, which possess constitutive nuclear factor erythroid 2-related factor 2 (NRF2) activity, were insensitive to plumbagin; however, inhibition of glucose transporter 1 (GLUT1) by small-molecule BAY-876 or inhibiting glucose-6-phosphate dehydrogenase (G6PD) by 6-aminonicotinamide (6-AN) overcame the plumbagin-resistance of KEAP1-mutant NSCLC cells. Taken together, this study elucidated the pharmacological mechanism of plumbagin by targeting TrxR1 and revealed the synergy effect of plumbagin and BAY-876, which may be helpful for applying naphthoquinone compounds to chemotherapy, particularly for treating KEAP1-mutant NSCLC cells.
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Highlights |
• | N-terminal redox motif is essential for TrxR1-mediated plumbagin redox cycling. |
• | Se-deficiency mutation of TrxR1 supports the high-efficiency plumbagin reduction. |
• | Plumbagin modifies the Sec498 site of TrxR1 and promotes the SecTRAPs generation. |
• | Glucose limitation sensitizes NSCLC cells and overcomes their resistance to plumbagin. |
Abbreviations : TrxR or TXNRD, Trx or TXN, TRP14, SOD, SecTRAPs, SECIS, Sec or U, Cys or C, ROS, PPP, OXPHOS, NSCLC, NRF2, NADPH, KEAP1, GR, GLUT, DTNB, DNCB, 1, 6-AN, 9
Keywords : Thioredoxin reductase 1, Plumbagin, Naphthoquinone, KEAP1 mutation, Non-small cell lung cancer (NSCLC), Glucose limitation
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Vol 146
Article 112546- février 2022 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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