Dataset Information

Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7.

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.

SUBMITTER: Ma L

PROVIDER: S-EPMC7058073 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7.

Ma Ling L Wang Zhangding Z Xie Mengyan M Quan Yunlin Y Zhu Weiyou W Yang Fengming F Zhao Chenhui C Fan Yu Y Fang Na N Jiang Huning H Wang Qiang Q Wang Shouyu S Zhou Jianwei J Chen Xiaofeng X Shu Yongqian Y

Cell death & disease 20200305 3

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 apo ...[more]

PMID: 32139670

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Project description:The prognosis of advanced non‑small cell lung cancer (NSCLC) is poor; therefore, identifying novel treatment strategies for patients with NSCLC is important. The present study aimed to investigate the efficacy of apatinib plus docetaxel vs. docetaxel alone, as well as their effects on regulating autophagy markers in patients with advanced NSCLC. Furthermore, it was evaluated whether apatinib sensitized chemoresistant NSCLC cells to docetaxel via regulating autophagy. A total of 39 patients with advanced NSCLC were consecutively enrolled and treated with apatinib plus docetaxel (n=19) or docetaxel alone (n=20) for four treatment cycles. The treatment response, adverse events and expression levels of autophagy markers [(light chain 3 α (LC3A) and Beclin‑1] were evaluated in tumor samples, which were obtained via biopsy, before treatment and after 2‑cycle treatment. In addition, in a mechanistic in vitro experiment, apatinib, docetaxel, the autophagy activator rapamycin and the autophagy inhibitor 3‑methyladenine (3‑MA) were used to treat docetaxel‑resistant A549 (A549/DTX) cells alone or in various combinations. The expression levels of LC3A, Beclin‑1, poly (ADP) ribose polymerase (PARP) and phosphorylated (p)‑AKT were detected via western blotting, while the cell apoptosis rate was detected with an Annexin V/PI assay. The overall remission rate (37 vs. 10%; P=0.047) and disease control rate (84 vs. 45%; P=0.011) were increased in the Apatinib plus docetaxel group compared with the Docetaxel group. Most of the adverse events were mild and tolerable, and there was no difference between the two groups except for total hypertension and hand‑foot syndrome, which were higher in the Apatinib plus docetaxel group). Compared with the levels prior to treatment, Beclin‑1 and LC3A remained unchanged post‑treatment in the Apatinib plus docetaxel group, while they were increased in the Docetaxel group. Docetaxel increased LC3A, Beclin‑1 and p‑AKT expression levels, PARP cleavage and the cell apoptosis rate in A549/DTX cells, and rapamycin further enhanced, while 3‑MA reduced these effects of docetaxel. Moreover, apatinib repressed LC3A, Beclin‑1, p‑AKT expression levels and promoted the cell apoptosis rate in A549/DTX cells and docetaxel‑treated A549/DTX cells. In conclusion, apatinib synergize the effect of docetaxel in treating patients with advanced NSCLC and chemoresistant NSCLC cells via inhibiting autophagy.

Project description:BackgroundAutophagy and ER stress are involved in maintaining some well-orchestrated mechanisms aimed at either restoring cellular homeostasis or performing cell death. Autophagy is a well-defined process which governs overall cellular stress outcomes. Selective degradation of the ER mediated by autophagy occurs through a specific type of autophagy called ER-phagy, which ensures ER protein homeostasis.MethodsImmunoblotting and RT-PCR were used to evaluate the expression of ATG5 and ATG7 in chondrocyte. Western blotting, Flow cytometry,immunofluorescence cell staining and confocal microscope were used to examine the effect of ATG5 and ATG7 on autophagy, ER stress, cell apoptosis and cell proliferation. Transmission electron microscope and confocal microscope were performed to visualize the autophagy flux and autolysosome formation. The role of ATG5 and ATG7 overexpression on the PERK pathway inhibitor were detected by immunoblotting and treatment with inhibitors.ResultsIn current study, we demonstrated that Tm-induced ER stress can activate autophagy while Rapamycin-induced autophagy can inhibit ER stress in chondrocyte. Autophagy related protein ATG5 or ATG7 can promote autophagy and inhibit ER stress individually, and their combined effect can further improve the autophagy enhancement and the ER stress repression. Moreover, ATG5, ATG7 and ATG5 + ATG7 lead cells into more S phase, increase the number of S phase and inhibit apoptosis as well. ATG5, ATG7 and ATG5 + ATG7 regulate autophagy, ER stress, apoptosis and cell cycle through PERK signaling, a vital UPR branch pathway.ConclusionsATG5 and ATG7 connect autophagy with ER stress through PERK signaling. The protective effect of ATG5/7 overexpression on chondrocyte survival relys on PERK signaling. The effect of siPERK and siNrf2 on the cytoprotective effect of ATG5/7 are of synergism, while the effect of siPERK and siATF4 are of antagonism. PERK signal may be the pivot for autophagy, ER homeostasis and ER-phagy in chondrocyte.

Dataset Information

Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7.

Publications

Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7.

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