All-trans-retinoic acid induces manganese superoxide dismutase in human neuroblastoma through NF-κB

Abstract

Retinoids are signaling molecules that are involved in proliferation, differentiation and apoptosis during development. Retinoids exert their effects, in part, by binding to nuclear receptors, thereby altering gene expression. Clinical use of retinoids in the treatment of neuroblastoma is of interest due to their success in management of acute promyelocytic leukemia. Using the SK-N-SH human neuroblastoma cell line we investigated the effect of the differentiation agent, all-trans-retinoic acid (ATRA) on manganese superoxide dismutase (MnSOD) expression, an enzyme previously shown to enhance differentiation in vitro. Manganese superoxide dismutase mRNA, protein and activity levels increased in a time dependent manner upon treatment with ATRA. Nuclear levels of the NFκB proteins, p50 and p65, increased within 24 h of ATRA administration. This increase paralleled the degradation of the cytoplasmic inhibitor, IκB-β. Furthermore an increase in DNA binding activity to a NFκB element occurred within a 342 base pair enhancer (I2E) of the SOD2 gene with 10 μM ATRA treatment. Reporter analysis showed that ATRA-mediated I2E dependent luciferase expression was attenuated upon mutation of the NFκB element, suggesting a contribution of this transcription factor in retinoid-mediated upregulation of MnSOD. This study identifies SOD2 to be a retinoid responsive gene and demonstrates activation of the NFκB pathway in response to ATRA treatment of SK-N-SH cells. These results suggest signaling events involving NFκB and SOD2 may contribute to the effects of retinoids used in cancer therapy.

Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

“…One of the ATRA-mediated signaling pathways is the activation of the transcription factor, NF-κB. [29][30][31] Consistent with these reports, the NF-κB repressor protein, inhibitor of NF-κB (IκB-α), level was decreased during ATRA-induced neuroblastoma treatment, and returned to normal levels when ATRA was replaced with DMSO ( Figure 2c). This observation was supported by NF-κΒ luciferase assay, where an increase in κB promoter activity upon ATRA treatment compared with DMSO-treated cells was observed (Figure 2d).…”

Heat stress upregulates chaperone heat shock protein 70 and antioxidant manganese superoxide dismutase through reactive oxygen species (ROS), p38MAPK, and Akt

“…Activated Akt functions upstream of the overexpression of both Hsp70 and MnSOD chronic/repetitive heat stress catalase upregulation is not observed (data not shown) indicating perhaps the predominant generation of reactive oxygen species other than H 2 O 2 . Recent studies (Kiningham et al 2008;Shilo et al 2008) have demonstrated that MnSOD expression may be controlled by a number of transcription factors. The elements which control the transcription of MnSOD in heat-shocked cells and are downstream from Akt activation by heat shock remain to be elucidated.…”

Upregulation of manganese superoxide dismutase (SOD2) is a common pathway for neuroendocrine differentiation in prostate cancer cells

“…31 All-trans retinoic acid has been shown to induce differentiation in neuroblastoma cells through the activation of NFjB, which in turn induces MnSOD expression. 32 MnSOD expression has also been associated to the developing rat brain and liver. 33 However, those studies only show a temporal relationship between differentiation and MnSOD upregulation, demonstrating that this is an early event in the cell differentiation process.…”