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.

Keywords: (NF-E2-related factor 2) Nrf2; antioxidant transcription factors; chemoresistance; oxidative stress.

Figure 1

Number of articles per year, reported on PubMed, entering the search filter: “oxidative stress AND cancer” (bar graph; Y-axis on the left side) or “oxidative stress AND cancer AND chemoresistance” (line graph; Y-axis on the right side) in title and/or abstract.

Figure 2

Oxidant and antioxidants in redox homeostasis in normal, cancer, and chemoresistant cancer cells. (A) Normal cells keep constant oxidant production and elimination to maintain a favorable redox balance. (B) Cancer cells exhibit higher steady-state levels of oxidant species, counterbalanced by increased antioxidant capacity. (C) Chemoresistant cancer cells up-regulate the antioxidant defenses to counteract oxidant species.

Figure 3

Mechanisms of control of Nrf2 activity.