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• W2295091179 abstract "Arsenic trioxide (ATO) is an effective treatment for acute promyelocytic leukemia (APL). While it is undergoing clinical trials for numerous malignancies including multiple myeloma, myelodysplastic syndrome, lymphoma and solid tumors, it has demonstrated only limited efficacy as a single agent. However, it may hold promise as part of a combination therapy. Thus investigation to elucidate the mechanisms of action underlying these clinical responses may lead to generation of rational combination therapies to increase its therapeutic spectrum. Previous work has described a pathway required for ATO-induced apoptosis in APL cells involving the generation of reactive oxygen species (ROS), and the subsequent induction of a specific mitogen-activated protein kinase (MAPK) cascade that includes both stress-activated protein kinase (SAPK)/ERK kinase 1 (SEK1) and c-Jun N-terminal kinases (JNK) activation. However, the link between ROS production and activation of SEK1 remains to be elucidated. Apoptosis signaling kinase 1 (ASK1) is a MAP3K upstream of SEK1 that has been implicated in the induction of stress-induced signaling.Using murine embryonic fibroblasts (MEFs) derived from ASK1-/- mice; we provide evidence that ASK1 is a strong mediator for ATO-induced apoptosis and JNK activation. In an APL cell line, we show that ATO activates ASK1 in a dose- and time-dependent manner. However, knockdown of ASK1 in APL cells enhanced susceptibility to ATO, undergoing apoptosis and growth inhibition more than their wild type counterparts. The same impact was observed in the knockdown of SEK1, a direct downstream MAP2K of ASK1, and the knockdown of ASK1 in MCF-7 cells, a human breast cancer cell line. This led us to postulate that ASK1 had a pro-apoptotic function in non-transformed fibroblasts, but was pro-survival in malignant cells. Indeed, transformation of ASK1-/- MEFs restored their sensitivity to ATO-induced apoptosis and growth inhibition. Taken together, these results suggest that ASK1 can have both pro-apoptotic and anti-apoptotic roles depending on the transformation state of the cells.One model of ASK1 regulation suggests that ASK1 is kept in an inactive form by reduced thioredoxin-1 (Trx1). During oxidative stress, Trx1 is oxidized and releases ASK1 for activation. Immunoprecipitation of ASK1 followed by immuoblotting for Trx1 in APL cells shows a strong basal association that is lost with ATO treatment. Furthermore, the activity of thioredoxin reductase 1 (TrxR1), an enzyme that converts oxidized Trx1 into reduced Trx1, is significantly decreased following ATO treatment. This suggests that ATO activates ASK1 signaling by ROS-mediated oxidation of Trx1 and by maintaining Trx1 in its oxidized state by decreasing TrxR1 activity. In addition, we show that inhibition of TrxR1 with the TrxR1 inhibitor Auranofin sensitizes APL cells to ATO-induced apoptosis. Overall, our results suggest that targeting Trx1 may enhance ATO-induced apoptosis in a novel combination therapy.%%%%L'arsenic trioxyde (ATO) est un…" @default.
• W2295091179 created "2016-06-24" @default.
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• W2295091179 date "2013-01-01" @default.
• W2295091179 modified "2023-09-23" @default.
• W2295091179 title "The role of ASK1 in arsenic trioxide-induced cell death" @default.
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