Mass spectrometry insights into interactions of selenoprotein P with auranofin and cisplatin

Lamarche, Jérémy; Bierła, Katarzyna; Ouerdane, Laurent; Szpunar, Joanna; Ronga, Luisa; Łobiński, Ryszard

doi:10.1039/d2ja00090c

Cited by 11 publications

(5 citation statements)

References 45 publications

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“…Once Auranofin enters the cell, the (triethylphosphoranylidene)gold separates from the carrying sugar and reacts with selenocysteine residues to form an Au-Se inhibitory adduct 43,44 . While Auranofin is typically considered an inhibitor of Thioredoxin Reductase 1 (TxnRD1), preventing oxidative protein folding and peroxiredoxin recycling to potently induce oxidative stress 45,46 , recent data demonstrate that the true mechanism of Auranofin is the nonspecific formation of Au-Se adducts, revealing Auranofin to be a broad selenoprotein inhibitor [47][48][49] -similar to our recharacterization of RSL3 (Figure 4A). To investigate the therapeutic potential of Auranofin in CRC we performed dose response curves across our CRC cell line panel.…”

Section: Auranofin a Selenoproteome Inhibitor Induces Oxidative Stres...supporting

confidence: 70%

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer

DeAngelo,

Dziechciarz,

Solanki

et al. 2024

Preprint

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Ferroptosis is an iron-dependent, non-apoptotic form of cell death resulting from the accumulation of lipid peroxides. Colorectal cancer (CRC) accumulates high levels of intracellular iron and reactive oxygen species (ROS), thereby sensitizing cells to ferroptosis. The selenoprotein glutathione peroxidase (GPx4) is a key enzyme in the detoxification of lipid peroxides and can be inhibited by the compound (S)-RSL3 ([1S,3R]-RSL3). However, the stereoisomer (R)-RSL3 ([1R,3R]-RSL3), which does not inhibit GPx4, exhibits equipotent activity to (S)-RSL3 across a panel of CRC cell lines. Utilizing CRC cell lines with an inducible knockdown of GPx4, we demonstrate that (S)-RSL3 sensitivity does not align with GPx4 dependency. Subsequently, a biotinylated (S)-RSL3 was then synthesized to perform affinity purification-mass spectrometry (AP-MS), revealing that (S)-RSL3 acts as a pan-inhibitor of the selenoproteome, targeting both the glutathione and thioredoxin peroxidase systems as well as multiple additional selenoproteins. To investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed further chemical and genetic approaches to disrupt selenoprotein function. The findings demonstrate that the selenoprotein inhibitor Auranofin can induce ferroptosis and/or oxidative cell death both in-vitro and in-vivo. Consistent with this data we observe that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translational incorporation of selenocysteine, is essential for CRC growth. In summary, our research elucidates the complex mechanisms underlying ferroptosis in CRC and reveals that modulation of the selenoproteome provides multiple new therapeutic targets and opportunities in CRC.

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Section: Auranofin a Selenoproteome Inhibitor Induces Oxidative Stres...supporting

confidence: 70%

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer

DeAngelo,

Dziechciarz,

Solanki

et al. 2024

Preprint

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“…An interesting paper deals on the reactivity of SelP with two metalloproteins: aurofin and cisplatin. 109 The SelP was first purified from human serum by sequential affinity chromatography by using two columns: an immobilised Co 2+ affinity (IMAC) and a heparin affinity column. The SelP was well separated from other Se-containing proteins (GPx and SeAl) by the IMAC column.…”

Section: Elemental Speciation Analysismentioning

confidence: 99%

Atomic spectrometry update: review of advances in elemental speciation

Clough

Harrington

Hill

et al. 2023

J. Anal. At. Spectrom.

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“…Indeed, the first step, involved in AF pharmacological activity, is the release of the thiosugar moiety. AF, once activated, can bind tightly to several biological targets, in particular, proteins containing free cysteines (Cys) − or selenocysteines (Sec), , producing cellular effects. AF, due to its antiproliferative properties in several tumoral models, became the reference compound for the emerging class of gold-based drugs …”

Section: Introductionmentioning

confidence: 99%

Mechanistic Evaluations of the Effects of Auranofin Triethylphosphine Replacement with a Trimethylphosphite Moiety

et al. 2023

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Auranofin, a gold(I)-based complex, is under clinical trials for application as an anticancer agent for the treatment of nonsmall-cell lung cancer and ovarian cancer. In the past years, different derivatives have been developed, modifying gold linear ligands in the search for new gold complexes endowed with a better pharmacological profile. Recently, a panel of four gold(I) complexes, inspired by the clinically established compound auranofin, was reported by our research group. As described, all compounds possess an [Au{P(OMe)3}]+ cationic moiety, in which the triethylphosphine of the parent compound auranofin was replaced with an oxygen-rich trimethylphosphite ligand. The gold(I) linear coordination geometry was complemented by Cl–, Br–, I–, and the auranofin-like thioglucose tetraacetate ligand. As previously reported, despite their close similarity to auranofin, the panel compounds exhibited some peculiar and distinctive features, such as lower log P values which can induce relevant differences in the overall pharmacokinetic profiles. To get better insight into the P–Au strength and stability, an extensive study was carried out for relevant biological models, including three different vasopressin peptide analogues and cysteine, using 31P NMR and LC-ESI-MS. A DFT computational study was also carried out for a better understanding of the theoretical fundamentals of the disclosed differences with regard to triethylphosphine parent compounds.

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Mass spectrometry insights into interactions of selenoprotein P with auranofin and cisplatin

Abstract: The reactivity of selenoprotein P (a serum selenoprotein containing 10 selenocysteine (SeCys), 17 cysteine (Cys) and 14 histidine (His) residues) with two metallodrugs (auranofin and cisplatin) was investigated. The selenoprotein...

Cited by 11 publications

References 45 publications

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer

Atomic spectrometry update: review of advances in elemental speciation

Mechanistic Evaluations of the Effects of Auranofin Triethylphosphine Replacement with a Trimethylphosphite Moiety

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