Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7
The positive results of the apatinib phase III trial have cast new light on treatment for patients with advanced gastric cancer (GC). However, in terms of safety, apatinib toxicities may lead to a dose modification or treatment interruption. Therefore, proper intervention is urgently needed to help...
Gespeichert in:
Veröffentlicht in: | Cell death & disease 2020-03, Vol.11 (3), p.169, Article 169 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | The positive results of the apatinib phase III trial have cast new light on treatment for patients with advanced gastric cancer (GC). However, in terms of safety, apatinib toxicities may lead to a dose modification or treatment interruption. Therefore, proper intervention is urgently needed to help patients benefit from apatinib treatment. In this study, we found that apatinib promoted autophagy activation via upregulation of ATG7 expression and autophagy inhibition enhanced apatinib-induced apoptosis. With microRNA and circular RNA-sequencing analyses of GC xenograft models, we demonstrated that
circRACGAP1
functioned as an endogenous sponge for
miR-3657
to inhibit its activity and further upregulate
ATG7
expression. Silencing of
circRACGAP1
inhibited apatinib-induced autophagy, which was rescued by
miR-3657
. Moreover, knockdown of
circRACGAP1
sensitized GC cells to apatinib via autophagy inhibition in vitro and in vivo. These findings provided the first evidence that the
circRACGAP1
-
miR-3657-ATG7
axis mediates a novel regulatory pathway critical for the regulation of apatinib sensitivity in GC. Thus, specific blockage of
circRACGAP1
may be a potential therapeutic strategy to reduce the toxicities of apatinib and enhance its therapeutic effect in human GC. |
---|---|
ISSN: | 2041-4889 2041-4889 |
DOI: | 10.1038/s41419-020-2352-0 |