ReferenceID 6019
Piperlongumine Inhibits Thioredoxin Reductase 1 by Targeting Selenocysteine Residues and Sensitizes Cancer Cells to Erastin
Antioxidants (Basel)
Piperlongumine, a natural alkaloid substance extracted from the fruit of the long pepper ( Piper longum Linn .), is known to inhibit the cytosolic thioredoxin reductase (TXNRD1 or TrxR1) and selectively kill cancer cells
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Record Fields
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- Reference Id
- 6019
- Evidence Id
- 22609
- Core Evidence Id
- 22609
- Source Reference Id
- 5301
- Herb2 Reference Id
- HBREF006098
- Subject Paper Key
- HBIN040107_35453395
- Pubmed Id
- 35453395
- Doi
- 10.3390/antiox11040710
- Paper Title
- Piperlongumine Inhibits Thioredoxin Reductase 1 by Targeting Selenocysteine Residues and Sensitizes Cancer Cells to Erastin
- Paper Abstract
- Piperlongumine, a natural alkaloid substance extracted from the fruit of the long pepper ( Piper longum Linn .), is known to inhibit the cytosolic thioredoxin reductase (TXNRD1 or TrxR1) and selectively kill cancer cells. However, the details and mechanism of the inhibition by piperlongumine against TXNRD1 remain unclear. In this study, based on the classical DTNB reducing assay, irreversible inhibition of recombinant TXNRD1 by piperlongumine was found and showed an apparent k inact value of 0.206 × 10 -3 µM -1 min -1 . Meanwhile, compared with the wild-type TXNRD1 (-GCUG), the UGA-truncated form (-GC) of TXNRD1 was resistant to piperlongumine, suggesting the preferential target of piperlongumine is the selenol (-SeH) at the C-terminal redox motif of the enzyme. Interestingly, the high concentration of piperlongumine-inhibited TXNRD1 showed that its Sec-dependent activity is decayed but its intrinsic NADPH oxidase activity is retained. Furthermore, piperlongumine did not induce ferroptosis in HCT116 cells at 10 µM, whereas significantly promoted erastin-induced lipid oxidation, which could be alleviated by supplying glutathione (GSH) or N-acetyl L-cysteine (NAC). However, restricting GSH synthesis by inhibiting glutaminase (GLS) using the small molecule inhibitor CB-839 only slightly enhanced erastin-induced cell death. Taken together, this study elucidates the molecular mechanism of the antitumor capacity of piperlongumine by targeting TXNRD1 and reveals the potential possibility of inhibiting TXNRD1 to strengthen cancer cells' ferroptosis.
- Journal
- Antioxidants (Basel)
- Publish Year
- 2022
- Experiment Subject
- hct116 cells
- Experiment Type
- Cell Experiment
- Phenotype Related
- Cancer
- Paper Title Cn
- Paper Title En
- Piperlongumine Inhibits Thioredoxin Reductase 1 by Targeting Selenocysteine Residues and Sensitizes Cancer Cells to Erastin
- Bilingual Status
- semi_complete