A diterpenoid derivate compound targets selenocysteine of thioredoxin reductases and induces Bax/Bak-independent apoptosis

Abstract

We have previously shown that the natural diterpenoid derivative S3 induced Bim upregulation and apoptosis in a Bax/Bak-independent manner. However, the exact molecular target(s) of S3 and the mechanism controlling Bim upregulation are still not clear. Here, we identify that S3 targets the selenoproteins TrxR1 and TrxR2 at the selenocysteine residue of the reactive center of the enzymes and inhibits their antioxidant activities. Consequently, cellular ROS is elevated, leading to the activation of FOXO3a, which contributes to Bim upregulation in Bax/Bak-deficient cells. Moreover, S3 retards tumor growth in subcutaneous xenograft tumors by inhibiting TrxR activity in vivo. Our studies delineate the signaling pathway controlling Bim upregulation, which results in Bax/Bak-independent apoptosis and provide evidence that the compounds can act as anticancer agents based on mammalian TrxRs inhibition.

Keywords: 15-oxospiramilactone; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; AP1; ASK1; Apoptosis; Bim; CBB; Cancer; Coomassie brilliant blue; DMEM; DNCB; DTNB; Dulbecco's modified Eagle's medium; GRs; HIF-1α; MEF; MTT; N-acetyl-l-cysteine; NAC; NF-κB; PI; ROS; S3; Sec; Thioredoxin reductase; Trx; TrxR; activator protein-1; apoptosis signal-regulating kinase 1; dinitrochlorobenzene; dithiobisnitrobenzoic acid; glutathione reductases; hypoxia-inducible factor 1α; mouse embryonic fibroblast; nuclear transcription factor κ; propidium iodide; reactive oxygen species; selenocysteine; thioredoxin; thioredoxin reductase.