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Cancer Cell. 2017 Nov 13;32(5):561-573.e6. doi: 10.1016/j.ccell.2017.09.008. Epub 2017 Oct 12.

iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding.

Author information

1
School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province 150001, China.
2
School of Chemistry, Harbin Institute of Technology, Harbin, Heilongjiang Province 150001, China.
3
Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150006, China.
4
School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province 150001, China; Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen 518055, China. Electronic address: huying@hit.edu.cn.

Abstract

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.

KEYWORDS:

Keap1; Nrf2; ROS; cancer growth; chemoresistance; iASPP; renal cell carcinoma

PMID:
29033244
DOI:
10.1016/j.ccell.2017.09.008
[Indexed for MEDLINE]
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