Nuclear factor erythroid-2 related factor-2 (Nrf2) is a transcription factor, widely considered the master regulator of the antioxidant response. Under normal condition, its inhibitor, the Kelch-like ECH-associated protein 1 (Keap1), binds Nrf2, causing its cytoplasmatic retention and mediating Nrf2 ubiquitination followed by proteasomal degradation; under oxidative stress, Nrf2 dissociates from Keap1, translocates into the nucleus, and induces the expression of genes bearing Antioxidant Responsive Element (ARE) in their promoters, such as phase II detoxifying enzymes and antioxidant genes. In these years several studies confirmed that Nrf2 has a cancer-protective activity via its cytoprotective functions; however, growing body of evidence showed that it is frequently activated in many resistant tumors, as an adaptative response to the increased oxidative stress. This activation makes cancer cells more resistant to drug treatments. Thus, its inhibition could sensitize tumor cells to pro-oxidant therapies, suggesting that the Nrf2 inhibition, through chemical inhibitors or RNA interference strategies, is a promising tool in cancer therapy. As observed in many cancers, Nrf2 plays a role in the progression of brain tumors, such as astrocytomas, multiforme glioblastomas, gliosarcomas, medulloblastomas, oligodendroglial and ependymal tumors. However, most of the research focusing on the mechanisms in the regulation of Nrf2, as well as on its potential value in the cancer treatment, have been carried out in adult glioblastomas. Thus, little is known about the role of Nrf2 in most of the common childhood brain tumors. Here, we summarize and discuss findings on Nrf2 in common pediatric CNS tumors, as well as the clinical perspectives in using Nrf2 inhibitors for cancer CNS treatment.

The Potential Therapeutic Target Nrf2 in Childhood Brain Tumors

Giuseppina Barrera
First
;
Martina Daga;CUCCI Marie Angele;Stefania Pizzimenti
Last
2017-01-01

Abstract

Nuclear factor erythroid-2 related factor-2 (Nrf2) is a transcription factor, widely considered the master regulator of the antioxidant response. Under normal condition, its inhibitor, the Kelch-like ECH-associated protein 1 (Keap1), binds Nrf2, causing its cytoplasmatic retention and mediating Nrf2 ubiquitination followed by proteasomal degradation; under oxidative stress, Nrf2 dissociates from Keap1, translocates into the nucleus, and induces the expression of genes bearing Antioxidant Responsive Element (ARE) in their promoters, such as phase II detoxifying enzymes and antioxidant genes. In these years several studies confirmed that Nrf2 has a cancer-protective activity via its cytoprotective functions; however, growing body of evidence showed that it is frequently activated in many resistant tumors, as an adaptative response to the increased oxidative stress. This activation makes cancer cells more resistant to drug treatments. Thus, its inhibition could sensitize tumor cells to pro-oxidant therapies, suggesting that the Nrf2 inhibition, through chemical inhibitors or RNA interference strategies, is a promising tool in cancer therapy. As observed in many cancers, Nrf2 plays a role in the progression of brain tumors, such as astrocytomas, multiforme glioblastomas, gliosarcomas, medulloblastomas, oligodendroglial and ependymal tumors. However, most of the research focusing on the mechanisms in the regulation of Nrf2, as well as on its potential value in the cancer treatment, have been carried out in adult glioblastomas. Thus, little is known about the role of Nrf2 in most of the common childhood brain tumors. Here, we summarize and discuss findings on Nrf2 in common pediatric CNS tumors, as well as the clinical perspectives in using Nrf2 inhibitors for cancer CNS treatment.
2017
5
11
17
http://www.synchropublisher.com/62-medical/journal-of-pediatric-oncology/1202-the-potential-therapeutic-target-nrf2-in-childhood-brain-tumors
Giuseppina Barrera, Martina Daga, CUCCI Marie Angele, Stefania Pizzimenti
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1677881
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