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

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.

Analysis in silico of the functional interaction between WNT5A and YAP/TEAD signaling in cancer

To date, most data regarding the crosstalk between the Wnt signaling pathway and the YAP/TAZ transcriptional coactivators focuses on the Wnt/β-catenin branch of the pathway. In contrast, the relationship between the non-canonical Wnt pathway and YAP/TAZ remains significantly less explored. Wnt5a is usually regarded as a prototypical non-canonical Wnt ligand, and its expression has been related to cancer progression. On the other hand, YAP/TAZ transcriptional coactivators act in concert with TEAD transcription factors to control gene expression. Although one article has shown previously that WNT5A is a YAP/TEAD target gene, there is a need for further evidence supporting this regulatory relationship, because a possible YAP/Wnt5a regulatory circuit might have profound implications for cancer biology. This article analyzes publicly available ChIP-Seq, gene expression, and protein expression data to explore this relationship, and shows that WNT5A might be a YAP/TEAD target gene in several contexts. Moreover, Wnt5a and YAP expression are significantly correlated in specific cancer types, suggesting that the crosstalk between YAP/TAZ and the Wnt pathway is more intricate than previously thought.