Redox balance influences differentiation status of neuroblastoma in the presence of all-trans retinoic acid

Abstract

Neuroblastoma is the most common extra-cranial solid tumor in childhood; and patients in stage IV of the disease have a high propensity for tumor recurrence. Retinoid therapy has been utilized as a means to induce differentiation of tumor cells and to inhibit relapse. In this study, the expression of a common neuronal differentiation marker [neurofilament M (NF-M)] in human SK-N-SH neuroblastoma cells treated with 10 μM all-trans retinoic acid (ATRA) showed significantly increased expression in accordance with reduced cell number. This was accompanied by an increase in MitoSOX and DCFH2 oxidation that could be indicative of increased steady-state levels of reactive oxygen species (ROS) such as O2•− and H2O2, which correlated with increased levels of MnSOD activity and immuno-reactive protein. Furthermore PEG-catalase inhibited the DCFH2 oxidation signal to a greater extent in the ATRA-treated cells (relative to controls) at 96 h indicating that as the cells became more differentiated, steady-state levels of H2O2 increased in the absence of increases in peroxide-scavenging antioxidants (i.e., glutathione, glutathione peroxidase, and catalase). In addition, ATRA-induced stimulation of NF-M at 48 and 72 h was enhanced by decreasing SOD activity using siRNA directed at MnSOD. Finally, treatment with ATRA for 96 h in the presence of MnSOD siRNA or PEG-catalase inhibited ATRA induced increases in NF-M expression. These results provide strong support for the hypothesis that changes in steady-state levels of O2•− and H2O2 significantly contribute to the process of ATRA-induced differentiation in neuroblastoma, and suggest that retinoid therapy for neuroblastoma could potentially be enhanced by redox-based manipulations of superoxide metabolism to improve patient outcome.

Silver Nanoparticles: Two-Faced Neuronal Differentiation-Inducing Material in Neuroblastoma (SH-SY5Y) Cells

“…Additionally, a significant suppression of the expression of antioxidant genes, such as SOD and CAT, was detected in AgNP-exposed cells, while they were significantly upregulated in RA-treated cells. The link between RA and the upregulation of SOD2 has also been reported previously [ 77 , 78 ]. Collectively, the results suggest that the mitochondria may be involved in AgNP-induced ROS generation, as consistent with previous reports showing the role of the mitochondria in AgNP-induced ROS generation [ 79 , 80 ].…”

Graphene Oxide–Silver Nanoparticles Nanocomposite Stimulates Differentiation in Human Neuroblastoma Cancer Cells (SH-SY5Y)

“…Our findings corroborated with earlier finding suggest that decreased catalase activity is associated with increased differentiation of human neuroblastoma cell line (IMR-32) [ 64 ]. Upon the treatment with ATRA, the level of anti-oxidant markers including GSH, (GPx), and catalase levels were significantly decreased following ATRA treatment compared to untreated group in several time points in human SK-N-SH neuroblastoma cells [ 65 , 66 ]. Recently, Dayem et al reported that moderate level ROS induced by AgNPs seems to be important factor for differentiation in SH-SY5Y cells [ 14 ].…”

Differentiation impairs Bach1 dependent HO-1 activation and increases sensitivity to oxidative stress in SH-SY5Y neuroblastoma cells

“…However, ROS can act as signaling molecules in neuronal cells too, for instance, as far as the differentiation activity of retinoic acid is concerned 4–6 . Thus, the ability to balance oxidative insults is crucial for neuronal cell survival.…”