Abstract
Thiacremonone (2, 4-dihydroxy-2, 5-dimethyl-thiophene-3-one) is an antioxidant substance as a novel sulfur compound generated from High-Temperature-High-Pressure-treated garlic. Peroxiredoxin 6 (PRDX6) is a member of peroxidases, and has glutathione peroxidase and calcium-independent phospholipase A2 (iPLA2) activities. Several studies have demonstrated that PRDX6 stimulates lung cancer cell growth via an increase of glutathione peroxidase activity. A docking model study and pull down assay showed that thiacremonone completely fits on the active site (cys-47) of glutathione peroxidase of PRDX6 and interacts with PRDX6. Thus, we investigated whether thiacremonone inhibits cell growth by blocking glutathione peroxidase of PRDX6 in the human lung cancer cells, A549 and NCI-H460. Thiacremonone (0–50 μg/ml) inhibited lung cancer cell growth in a concentration dependent manner through induction of apoptotic cell death accompanied by induction of cleaved caspase-3, -8, -9, Bax, p21 and p53, but decrease of xIAP, cIAP and Bcl2 expression. Thiacremonone further inhibited glutathione peroxidase activity in lung cancer cells. However, the cell growth inhibitory effect of thiacremonone was not observed in the lung cancer cells transfected with mutant PRDX6 (C47S) and in the presence of dithiothreitol and glutathione. In an allograft in vivo model, thiacremonone (30 mg/kg) also inhibited tumor growth accompanied with the reduction of PRDX6 expression and glutathione peroxidase activity, but increased expression of cleaved caspase-3, -8, -9, Bax, p21 and p53. These data indicate that thiacremonone inhibits tumor growth via inhibition of glutathione peroxidase activity of PRDX6 through interaction. These data suggest that thiacremonone may have potentially beneficial effects in lung cancer.
Highlights
Peroxiredoxins (PRDXs) are a family of peroxidases as antioxidant enzymes [1,2]
The results indicated that thiacremonone bound with recombinant Peroxiredoxin 6 (PRDX6) protein or cell lysates containing PRDX6 protein from human NCI-H460 lung cancer cells. (Fig. 1B and C)
We found decreased binding of thiacremonone with mutant PRDX6 C47S compared to PRDX6
Summary
Peroxiredoxins (PRDXs) are a family of peroxidases as antioxidant enzymes [1,2]. They are divided into two classes [3]. The 2-Cys group includes PRDX1-5, whereas PRDX6 is only a member of the 1-Cys group. PRDXs are a family of peroxidases that destroy peroxides using conserved cysteine residues in the catalytic center [4]. Among the six mammalian members of this family, PRDX6 is the only member that has glutathione peroxidase and calciumindependent phospholipase A2 (iPLA2) activities [5]. The antioxidant response element (ARE) in the prdx promoter region, a cis-acting regulator element, is activated by oxidative stress [8]. Transcription of the PRDX6 gene is regulated by nuclear factor erythroid 2-related factors 1, 2, and 3 (Nrf, Nrf, and Nrf3) as transcription factors via binding to the ARE [9]
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