1.
ROS Signaling-Mediated Novel Biological Targets: Brf1 and RNA Pol III Genes.
Zheng, L, Lin, Y, Zhong, S
Oxidative medicine and cellular longevity. 2021;:5888432
Abstract
Biomolecule metabolism produces ROS (reactive oxygen species) under physiological and pathophysiological conditions. Dietary factors (alcohol) and carcinogens (EGF, DEN, and MNNG) also induce the release of ROS. ROS often causes cell stress and tissue injury, eventually resulting in disorders or diseases of the body through different signaling pathways. Normal metabolism of protein is critically important to maintain cellular function and body health. Brf1 (transcript factor II B-related factor 1) and its target genes, RNA Pol III genes (RNA polymerase III-dependent genes), control the process of protein synthesis. Studies have demonstrated that the deregulation of Brf1 and its target genes is tightly linked to cell proliferation, cell transformation, tumor development, and human cancers, while alcohol, EGF, DEN, and MNNG are able to induce the deregulation of these genes through different signaling pathways. Therefore, it is very important to emphasize the roles of these signaling events mediating the processes of Brf1 and RNA Pol III gene transcription. In the present paper, we mainly summarize our studies on signaling events which mediate the deregulation of these genes in the past dozen years. These studies indicate that Brf1 and RNA Pol III genes are novel biological targets of ROS.
2.
ROS and CHOP are critical for dibenzylideneacetone to sensitize tumor cells to TRAIL through induction of death receptors and downregulation of cell survival proteins.
Prasad, S, Yadav, VR, Ravindran, J, Aggarwal, BB
Cancer research. 2011;(2):538-49
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Abstract
Because tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells, it is being tested in cancer patients. Unfortunately, patients develop resistance to the cytokine, therefore, agents that can sensitize cells to TRAIL are urgently needed. In this study, we investigated whether dibenzylideneacetone (DBA) can sensitize cancer cells to TRAIL and potentiates TRAIL-induced apoptosis. As indicated by accumulation of the membrane phospholipid phosphatidylserine, DNA breaks, intracellular esterase activity, and activation of caspase-8, -9, and -3, we concluded that DBA potentiated TRAIL-induced apoptosis in colon cancer cells. DBA also converted TRAIL resistant-cells to TRAIL-sensitive. When examined for the mechanism, we found that DBA decreased the expression of antiapoptotic proteins and decoy receptor-2 and increased proapoptotic proteins. DBA also induced both death receptor (DR)-5 and DR4. Knockdown of DR5 and DR4 by small interfering RNA (SiRNA) reduced the sensitizing effect of DBA on TRAIL-induced apoptosis. In addition, DBA increased the expression of CHOP proteins. Knockdown of CHOP by siRNA decreased the induction of DBA-induced DR5 expression and apoptosis. Induction of receptors by DBA, however, was p53-independent, as deletion of p53 had no effect on receptor induction. We observed that DBA-induced induction of DR5 and DR4 was mediated through generation of reactive oxygen species (ROS), as N-acetylcysteine blocked the induction of death receptors and suppression of cell survival proteins by DBA. Overall, our results show that DBA potentiates TRAIL-induced apoptosis through downregulation of cell survival proteins and upregulation of death receptors via activation of ROS and CHOP mediated pathways.
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Gamma-tocotrienol promotes TRAIL-induced apoptosis through reactive oxygen species/extracellular signal-regulated kinase/p53-mediated upregulation of death receptors.
Kannappan, R, Ravindran, J, Prasad, S, Sung, B, Yadav, VR, Reuter, S, Chaturvedi, MM, Aggarwal, BB
Molecular cancer therapeutics. 2010;(8):2196-207
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is in clinical trials for cancer therapy, but its anticancer potential is limited by the development of resistance. We investigated the ability of tocotrienol (T3), an unsaturated vitamin E present in palm oil, rice bran, barley, oats, and wheat germ, to sensitize tumor cells to TRAIL. Results from esterase staining, colony formation, caspase activation, and sub-G(1) cell cycle arrest revealed that gamma-T3 can sensitize human colon cancer cells to TRAIL. When examined for the mechanism, we found that gamma-T3 significantly downregulated the expression of antiapoptotic proteins (c-IAP2 and Bcl-xL). We also found that gamma-T3, but not tocopherol, induced the expression of the TRAIL receptors death receptor (DR)-4 and DR5. This induction was not cell type specific, as upregulation was also found in pancreatic, kidney, and leukemic cells. Upregulation of DRs by gamma-T3 required the production of reactive oxygen species (ROS), and sequestering of ROS abolished both upregulation of the receptors and potentiation of TRAIL-induced apoptosis. Induction of DRs by gamma-T3 also required activation of extracellular signal-regulated kinase 1 (ERK1), as silencing of ERK1 by specific siRNA abrogated the upregulation of TRAIL receptors. Further, induction of DRs by gamma-T3 required the expression of p53 and Bax, as no induction of the receptors was found in colon cancer cells with deletion of these genes. Overall, our results show that gamma-T3 sensitizes tumor cells to TRAIL by upregulating DRs through the ROS/ERK/p53 pathway and by downregulating cell survival proteins.