Control of Oxidative Stress in Cancer Chemoresistance: Spotlight on Nrf2 Role

Abstract

Chemoresistance represents the main obstacle to cancer treatment with both conventional and targeted therapy. Beyond specific molecular alterations, which can lead to targeted therapy, metabolic remodeling, including the control of redox status, plays an important role in cancer cell survival following therapy. Although cancer cells generally have a high basal reactive oxygen species (ROS) level, which makes them more susceptible than normal cells to a further increase of ROS, chemoresistant cancer cells become highly adapted to intrinsic or drug-induced oxidative stress by upregulating their antioxidant systems. The antioxidant response is principally mediated by the transcription factor Nrf2, which has been considered the master regulator of antioxidant and cytoprotective genes. Nrf2 expression is often increased in several types of chemoresistant cancer cells, and its expression is mediated by diverse mechanisms. In addition to Nrf2, other transcription factors and transcriptional coactivators can participate to maintain the high antioxidant levels in chemo and radio-resistant cancer cells. The control of expression and function of these molecules has been recently deepened to identify which of these could be used as a new therapeutic target in the treatment of tumors resistant to conventional therapy. In this review, we report the more recent advances in the study of Nrf2 regulation in chemoresistant cancers and the role played by other transcription factors and transcriptional coactivators in the control of antioxidant responses in chemoresistant cancer cells.

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

“…Mutations can also occur in the principal Nrf2 repressor, Keap1 or component of the E3 ubiquitin-ligase complex Cullin 3 (CUL3), with loss of function that renders these factors unable to bind Nrf2 and thus result in persistent Nrf2 activation [ 68 ].…”

Oxidative Stress-Related Mechanisms in Melanoma and in the Acquired Resistance to Targeted Therapies

“…A mountain of evidence has suggested that redox imbalance and resulting lipid peroxidation products play an important role in cancer development, progression, metastasis, and chemoresistance. These findings, excellently presented in several reviews [ 56 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ], are far from being unique. For instance, scientists have highlighted some paradoxes relating to the two faces of ROS, which are able to both promote and suppress cancer [ 74 ].…”

“…Recently, in a large cohort of melanoma tumor samples with different degrees of malignancy, it was demonstrated that there was no correlation between immunostaining of the Nrf2 protein and mRNA expression levels [ 147 ]. Thus, very likely, post-translational mechanisms can account for the Nrf2 activation in melanoma [ 73 ]. Among these mechanisms, short noncoding RNAs, in particular microRNAs (miRNAs), are gaining attention for their ability to control gene expression.…”

Antioxidant Therapy in Cancer: Rationale and Progress

“…However, treatment with NRF2 activators may inactivate drug-induced oxidative stress that normally would result in cell death. Therefore, it is necessary to monitor their clinical efficacy, given that the activation of NRF2 may contribute to the development of chemoresistance [ 138 , 139 ]. Taken together, NRF2 activators have shown potential for cancer therapy, but further investigations are also needed to demonstrate their clinical efficacy, especially in combination with chemotherapeutic drugs.…”