Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7
Open Access
- 5 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (3), 1-18
- https://doi.org/10.1038/s41419-020-2352-0
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.Keywords
This publication has 62 references indexed in Scilit:
- Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastasesRadiation Oncology, 2013
- The Autophagy Inhibitor Chloroquine Overcomes the Innate Resistance of Wild-Type EGFR Non-Small-Cell Lung Cancer Cells to ErlotinibJournal of Thoracic Oncology, 2013
- Survival from digestive cancer in emerging countries in Asia and AfricaEuropean Journal of Gastroenterology & Hepatology, 2012
- YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor‐2 tyrosine kinase with potent activity in vitro and in vivoCancer Science, 2011
- Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trialThe Lancet, 2010
- MicroRNAs: Target Recognition and Regulatory FunctionsCell, 2009
- Self-eating and self-killing: crosstalk between autophagy and apoptosisNature Reviews Molecular Cell Biology, 2007
- Autophagy: dual roles in life and death?Nature Reviews Molecular Cell Biology, 2005
- Mammalian Target of Rapamycin (mTOR): Pro- and Anti-ApoptoticCell Death & Differentiation, 2002
- Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cellsNature, 1979