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.
Highlights
Drug resistance, which occurs in most types of cancer, is a major problem in the treatment of cancer patients
Beyond specific molecular alterations, which can lead to targeted therapy, a mountain of evidence has suggested that the regulation of redox status plays an important role in cancer cell survival to the therapy [3,4]
We demonstrated that the downregulation of xCT, altered cancer stem cells (CSC) intracellular redox balance, suggesting that xCT plays a functional role in CSC biology [32]
Summary
Drug resistance, which occurs in most types of cancer, is a major problem in the treatment of cancer patients. The intrinsic resistance includes aberrations of signals downstream or upstream of the targeted proteins leading to the acquisition of cancer hallmarks, while acquired resistance is inclined to preserve the original alterations and develop additional alterations that can adapt cancer cells to resist further drug treatments [2]. Beyond specific molecular alterations, which can lead to targeted therapy, a mountain of evidence has suggested that the regulation of redox status plays an important role in cancer cell survival to the therapy [3,4]. We examined diverse molecular and biochemical changes involved in increasing the antioxidant of chemoresistant tumors. We examined diversepotential molecular and biochemical changes involved in increasing the antioxidant potential chemoresistant tumors
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