Upregulation of peroxiredoxin III in doxorubicin-induced cytotoxicity and the FoxO3a-dependent expression in H9c2 cardiac cells

Abstract

Doxorubicin (DOX) is an efficient drug used in cancer therapy; however, it produces reactive oxygen species (ROS) that induce severe cytotoxicity, limiting its clinical application. The aim of the present study was to investigate the role of peroxiredoxin III (Prx III) in DOX-induced H9c2 cell injuries. Following DOX treatment, the expression of phosphorylated-FoxO3a (p-FoxO3a) was decreased and Prx III expression was increased in H9c2 cells. In order to detect whether oxidative stress was involved in the induction of Prx III expression by FoxO3a, exogenous HO was used to induce oxidative stress in the H9c2 cells. Apoptosis of H9c2 cardiomyocytes was assessed using methyl thiazolyl tetrazolium assay and Hoechst staining. The levels of Prx III and p-FoxO3a were evaluated using western blot analysis. As expected, HO was found to mimic the effect of DOX, decreasing the expression of p-FoxO3a and increasing the expression of Prx III. In addition, the study evaluated whether the transcription factor FoxO3a was essential for the expression of Prx III. Pretreatment of H9c2 cells with N-acetyl-L-cysteine (NAC), a scavenger of ROS, prior to exposure to DOX dramatically increased the phosphorylation of FoxO3a and led to a marked reduction in Prx III expression in the H9c2 cells. In conclusion, the results of the current study suggest that FoxO3a mediates the expression of Prx III in DOX-induced injuries.

The Preventive Effects and Mode of Actions of Ulva Fasciata Synthesized Silver Nanoparticles in Doxorubicin-Induced Hepatotoxicity in Wistar Rats

“…The involvement of doxorubicin in the production of ROS has been widely accepted as the mechanism of action of doxorubicin-induced cardiotoxicity and hepatotoxicity [111,112,113,114]. The present study strongly support this elucidation as the present results showed a significant increase of LPO product and a significant decrease in GSH content and SOD, GST and GPx activities in liver, kidney and heart as a result of doxorubicin administration.…”

Up-regulation of peroxiredoxin 3 by high-risk human papillomavirus in cervical cancer cells

“…In lung squamous cell carcinoma, PRX3 is over-expressed in an Nrf2 dependent manner, which indicates a potentially important role of the Nrf2-PRX3 pathway in the tumor [16]. Chiribau et al reported that FOXO3A mediated PRX3 expression resulting in the resistance to oxidative stress in human cardiac fibroblasts [17], which was confirmed by other researchers in pheochromocytoma cells, cardiac cells, and endothelial cells respectively [18][19][20]. In addition, a study conducted by Cunniff et al reported the co-existence of cytoplasmic FOXM1 and mitochondrial PRX3 in mesothelioma cells [21].…”

Peroxiredoxins—The Underrated Actors during Virus-Induced Oxidative Stress

“…To date, a wide array of transcription factors have been shown to regulate transcription of their genes ( Table 2 ). They include Nrf2 [ 62 ], subunits of NF-κB [ 63 ], cMyc [ 64 ], AP-1 [ 65 ], specificity protein 1 (Sp1) [ 66 ], CCAAT/enhancer-binding protein β (C/EBPβ) [ 67 ], FoxO3a [ 68 ], glucocorticoid receptor [ 69 ], PGC-1α [ 70 ], GATA-binding protein 1 [ 71 ], nuclear respiratory factors 1 [ 72 ] and 2/GABP [ 73 ], as well as repressors, such as KLF9 [ 74 , 75 ] or Nrf3 [ 76 ].…”

“…Another transcription factor that controls the expression of several peroxiredoxins is FoxO3a that has multiple functions in a cell and whose functions are modulated by various protein kinases that affect its intracellular localization and activity [ 85 ]. To date it is accepted that FoxO3a regulates expression of Prdx 2 [ 86 ], 3 [ 68 , 70 , 87 ], and 5 [ 70 ]. In the case of peroxiredoxin 3, this transcription factor controls both constitutive and inducible expression.…”

“…In the case of peroxiredoxin 3, this transcription factor controls both constitutive and inducible expression. Induction of Prdx3 in response to cytotoxic agents, such as doxorubicin, is achieved via downregulation of FoxO3a phosphorylation [ 68 ] which is typical for its control by the PI3K/AKT pathway [ 85 ]. In addition, expression of Prdx3, as well as Prdx5, is regulated by FoxO3a in a complex with the mitochondrial fasting-inducible peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and in its turn is controlled by the sirtuin 1 (SirT1) [ 70 ].…”