Barrera Giuseppina, Cucci Marie Angele, Grattarola Margherita, Dianzani Chiara, Muzio Giuliana, Pizzimenti Stefania
Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Italy.
Department of Scienza e Tecnologia del Farmaco, University of Turin, Via Pietro Giuria 11, 10125 Turin, Italy.
Antioxidants (Basel). 2021 Mar 25;10(4):510. doi: 10.3390/antiox10040510.
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.
化疗耐药是传统疗法和靶向疗法治疗癌症的主要障碍。除了可导致靶向治疗的特定分子改变外，包括氧化还原状态控制在内的代谢重塑在治疗后的癌细胞存活中起着重要作用。尽管癌细胞通常具有较高的基础活性氧（ROS）水平，这使得它们比正常细胞更容易受到ROS进一步增加的影响，但化疗耐药癌细胞通过上调其抗氧化系统，对内在或药物诱导的氧化应激高度适应。抗氧化反应主要由转录因子Nrf2介导，Nrf2被认为是抗氧化和细胞保护基因的主要调节因子。Nrf2的表达在几种类型的化疗耐药癌细胞中通常会增加，并且其表达由多种机制介导。除了Nrf2之外，其他转录因子和转录共激活因子也可以参与维持化疗和放疗耐药癌细胞中的高抗氧化水平。最近对这些分子的表达和功能的控制进行了深入研究，以确定其中哪些可作为治疗对传统疗法耐药肿瘤的新治疗靶点。在这篇综述中，我们报告了化疗耐药癌症中Nrf2调控研究的最新进展，以及其他转录因子和转录共激活因子在控制化疗耐药癌细胞抗氧化反应中所起的作用。
