The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation.
Thioredoxin reductase (TrxR) is a key selenoprotein antioxidant enzyme and a potential target for anti-cancer drugs. One potent inhibitor of TrxR is the gold (I) compound auranofin, which can trigger mitochondrial-dependent apoptosis pathways. The exact mechanism of apoptosis induction by auranofin is not yet clear, but there are indications that mitochondrial oxidative stress is a central event. We assessed the redox state of the peroxiredoxins (Prxs) in Jurkat T-lymphoma cells treated with auranofin, and found that mitochondrial Prx3 was considerably more sensitive to oxidation than the cytosolic Prx1 and 2, indicating selective mitochondrial stress. Prx3 oxidation was detected at apoptotic doses of auranofin in several cell types, and occurred before other mitochondrial events including cytochrome c release and mitochondrial depolarisation. Auranofin was also able to sensitise U937 cells to TNF-alpha-mediated apoptosis. Auranofin-induced apoptosis was effectively blocked by the overexpression of Bcl-2, and Bax/Bak deficient mouse embryonic fibroblasts were also resistant to apoptosis, indicating a central role for the pro-apoptotic proteins of this family in auranofin-triggered apoptosis. Auranofin exposure inhibited the proliferation of apoptosis-resistant cells, and at higher doses of auranofin could cause cell death through necrosis. We conclude that auranofin induces apoptosis in cells through a Bax/Bak-dependent mechanism associated with selective disruption of mitochondrial redox homeostasis in conjunction with oxidation of Prx3.
Cox
Andrew G
AG
Free Radical Research Group, Department of Pathology, University of Otago, Christchurch, New Zealand.
Brown
Kristin K
KK
Arner
Elias S J
ES
Hampton
Mark B
MB
D000818:Animals; D017209:Apoptosis; D001310:Auranofin / Q000494:pharmacology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D061105:Peroxiredoxin III; D054464:Peroxiredoxins / Q000378:metabolism*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020298:U937 Cells; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000502:physiology*
C494772:BAK1 protein, human; C494826:BAX protein, human; D024101:Mitochondrial Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D001310:Auranofin; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D013880:Thioredoxin-Disulfide Reductase