LncRNA SLC7A11-AS1 Promotes Chemoresistance by Blocking SCF?-TRCP-Mediated Degradation of NRF2 in Pancreatic Cancer.

ABSTRACT: Drug resistance is the major obstacle of gemcitabine-based chemotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC). Many long non-coding RNAs (lncRNAs) are reported to play vital roles in cancer initiation and progression. Here, we report that lncRNA SLC7A11-AS1 is involved in gemcitabine resistance of PDAC. SLC7A11-AS1 is overexpressed in PDAC tissues and gemcitabine-resistant cell lines. Knockdown of SLC7A11-AS1 weakens the PDAC stemness and potentiates the sensitivity of resistant PDAC cells toward gemcitabine in vitro and in vivo. SLC7A11-AS1 promotes chemoresistance through reducing intracellular reactive oxygen species (ROS) by stabilizing nuclear factor erythroid-2-related factor 2 (NRF2), the key regulator in antioxidant defense. Mechanically, SLC7A11-AS1 is co-localized with ?-TRCP1 in the nucleus. The exon 3 of SLC7A11-AS1 interacts with the F-box motif of ?-TRCP1, the critical domain that recruits ?-TRCP1 to the SCF?-TRCP E3 complex. This interaction prevents the consequent ubiquitination and proteasomal degradation of NRF2 in the nucleus. Our results demonstrate that the overexpression of SLC7A11-AS1 in gemcitabine-resistant PDAC cells can scavenge ROS by blocking SCF?-TRCP-mediated ubiquitination and degradation of NRF2, leading to a low level of intracellular ROS, which is required for the maintenance of cancer stemness. These findings suggest SLC7A11-AS1 as a therapeutic target to overcome gemcitabine resistance for PDAC treatment.

SUBMITTER: Yang Q 

PROVIDER: S-EPMC7013141 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature