1. iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding
- Author
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Miao Yu, Wenjie Ge, Huayi Li, Yiwei Cheng, Shijian Jiang, Xuting Xue, Cheng Zhang, Yifu Zhu, Xingwen Wang, Ying Hu, Kunming Zhao, and Mengmeng He
- Subjects
0301 basic medicine ,Cancer Research ,Cell signaling ,NF-E2-Related Factor 2 ,Blotting, Western ,Drug resistance ,Biology ,medicine.disease_cause ,digestive system ,environment and public health ,Antioxidants ,03 medical and health sciences ,Transactivation ,0302 clinical medicine ,Ubiquitin ,Cell Line, Tumor ,Neoplasms ,medicine ,Humans ,Cytotoxic T cell ,Cell Proliferation ,chemistry.chemical_classification ,Reactive oxygen species ,Kelch-Like ECH-Associated Protein 1 ,Intracellular Signaling Peptides and Proteins ,respiratory system ,HCT116 Cells ,KEAP1 ,Cell biology ,Repressor Proteins ,030104 developmental biology ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,RNA Interference ,Tumor Suppressor Protein p53 ,Reactive Oxygen Species ,Carcinogenesis ,Protein Binding - Abstract
Summary Reactive oxygen species (ROS) have emerged as important signaling molecules that play crucial roles in carcinogenesis and cytotoxic responses. Nrf2 is the master regulator of ROS balance. Thus, uncovering mechanisms of Nrf2 regulation is important for the development of alternative treatment strategies for cancers. Here, we demonstrate that iASPP, a known p53 inhibitor, lowers ROS independently of p53. Mechanistically, iASPP competes with Nrf2 for Keap1 binding via a DLT motif, leading to decreased Nrf2 ubiquitination and increased Nrf2 accumulation, nuclear translocation, and antioxidative transactivation. This iASPP-Keap1-Nrf2 axis promotes cancer growth and drug resistance both in vitro and in vivo . Thus, iASPP is an antioxidative factor and represents a promising target to improve cancer treatment, regardless of p53 status.
- Published
- 2017