Abstract:
: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.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Ma L,Wang Z,Xie M,Quan Y,Zhu W,Yang F,Zhao C,Fan Y,Fang N,Jiang H,Wang Q,Wang S,Zhou J,Chen X,Shu Ydoi
10.1038/s41419-020-2352-0subject
Has Abstractpub_date
2020-03-05 00:00:00pages
169issue
3issn
2041-4889pii
10.1038/s41419-020-2352-0journal_volume
11pub_type
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