In:
Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 71, No. 6 ( 2020-06), p. 2005-2022
Abstract:
Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5‐mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression. Approach and Results RMP‐overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch‐like ECH‐associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP‐KEAP1‐NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis. Conclusion These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies.
Type of Medium:
Online Resource
ISSN:
0270-9139
,
1527-3350
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2020
detail.hit.zdb_id:
1472120-X