| First Author | Yoo MH | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 9 | Pages | e71427 |
| PubMed ID | 24039713 | Mgi Jnum | J:206399 |
| Mgi Id | MGI:5550190 | Doi | 10.1371/journal.pone.0071427 |
| Citation | Yoo MH, et al. (2013) Abrogated thioredoxin system causes increased sensitivity to TNF-alpha-induced apoptosis via enrichment of p-ERK 1/2 in the nucleus. PLoS One 8(9):e71427 |
| abstractText | Thioredoxin (Trx) and thioredoxin reductase 1 (TR1) are among the major redox regulators in mammalian cells and have a wide variety of roles, including removal of intracellular reactive oxygen species (ROS) and prevention of cell death. Tumor necrosis factor-alpha (TNF-alpha) induces cancer cell death. Although ROS have been proposed to participate in this process, the role of the thioredoxin system in TNF-alpha stimulated cell death remains unclear. We investigated the possibility that the thioredoxin system protects against TNF-alpha-induced cancer cell death by examining whether TR1/Trx1 status controls TNF-alpha-induced apoptosis in EMT6 murine breast cancer cells. TR1-deficient cells were more sensitive to TNF-alpha than control cells. Increased sensitivity to TNF-alpha was most pronounced in Trx1-deficient cells. TNF-alpha-induced nuclear localization of phosphorylated ERK 1/2 (p-ERK 1/2) correlated with increased apoptosis in TR1- and Trx1-deficient cells, suggesting a pro-apoptotic role for nuclear p-ERK 1/2 in TNF-alpha-induced apoptosis. In addition, phosphoinositide 3-kinase (PI3K) inhibition dramatically reduced TNF-alpha-stimulated apoptosis and nuclear localization of p-ERK 1/2. In contrast, inhibition of ROS, MEK, JNK, or p38 did not significantly alter p-ERK 1/2 localization or apoptosis in TR1- and Trx1-deficient cells compared to control cells. Further, NF-kappaB p65 localization was not changed in TR1- and Trx1-deficient cells in response to TNF-alpha relative to control cells. Our data suggest that the thioredoxin system plays a critical role in protecting against TNF-alpha-induced apoptosis by regulating the levels of nuclear p-ERK 1/2 in a PI3K-dependent manner. |
