miR-21 modulates cisplatin resistance of gastric cancer cells by inhibiting autophagy via the PI3K/Akt/mTOR pathway

Abstract

Resistance to cisplatin (DDP) remains a major obstacle in the control of gastric cancer (GC) progression. A previous study revealed that microRNA-21 (miR-21) contributes to DDP resistance in GC cells via the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. The aim of the current study was to explore the mechanisms underlying the cytoprotective function of miR-21. In this study, DDP-resistant GC cells were obtained by continuous exposure of human gastric adenocarcinoma cells to increasing concentrations of DDP. Western blot analysis was used to evaluate activation of the PI3K/Akt/mechanistic target of rapamycin kinase (mTOR) pathway. The level of miR-21 was altered by transfection of miR-21 mimic and inhibitor. Autophagy was assessed by detecting autophagosome formation, Beclin-1 and LC3 expression. An Annexin V-propidium iodide assay was performed to estimate the survival and death of GC cells. GC cells became refractory to the growth inhibition and apoptosis induced by DDP treatment, activation of Akt and mTOR were increased in DDP-resistant GC cells. Inhibition of autophagy decreased the sensitivity of GC cells to DDP, and autophagy induction produced the opposite effect. DDP-resistant GC cells expressed higher levels of miR-21 compared with the parent cells. Transfection of GC cells with miR-21 mimics contributed to restored DDP resistance by suppressing autophagy, while miR-21 inhibitor sensitized DDP-resistant GC cells by promoting autophagy. In conclusion, the results demonstrated that miR-21 is associated with DDP resistance in GC cells by inhibiting autophagy via the PI3K/Akt/mTOR pathway, and autophagy inducers could be therapeutic targets for the effective treatment of DDP resistance in GC.

Long non‐coding RNA MEG3 promotes autophagy and apoptosis of nasopharyngeal carcinoma cells via PTEN up‐regulation by binding to microRNA‐21

“…Although the anti‐autophagic function of miR‐21 has been elaborated in the hypoxia/reoxygenation‐exposed cardiomyocytes, 28 and renal tubular epithelial cells during renal ischaemia‐reperfusion, 29 its involvement in the human cancer cells remains largely unknown. miR‐21 was recently proposed as an inhibitor of autophagy in gastric cancer and therefore to enhance drug resistance 30 . The present study emphasized the tumour‐promotive role of miR‐21 in NPC by suppressing the cell autophagy.…”

hsa_circ_0000520 influences herceptin resistance in gastric cancer cells through PI3K‐Akt signaling pathway

“…Hsa_circ_0010882 also activates PI3K/ Akt signaling and promotes gastric cancer development 25 . Previous studies p‐PI3K can activate Akt to form p‐Akt, and then participate in the process of gastric cancer development and development 26‐30 . It was shown p‐PI3K and p‐Akt were reduced after Herceptin treatment in gastric cancer cells, and hsa_circ_0000520 overexpression could restrain p‐PI3K and p‐Akt level.…”

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

“…Tian et al (2018) have suggested that miR-361-5p negatively regulates the expression of FOXM1, which further causes an increase in the expression of p-AKT and mTOR, the inhibition of autophagy, and the enhanced sensitivity of gastric cancer cells to Docetaxel (DOC) in vitro. Gu et al (2020) have found that miR-21 overexpression can increase the phosphorylation of AKT and mTOR, inhibit autophagy, and induce DDP resistance. It has been further demonstrated that the knockdown of miR-21 can promote autophagy and then sensitize DDP-resistant gastric cancer cell lines to DDP (Gu et al, 2020).…”

“…Gu et al (2020) have found that miR-21 overexpression can increase the phosphorylation of AKT and mTOR, inhibit autophagy, and induce DDP resistance. It has been further demonstrated that the knockdown of miR-21 can promote autophagy and then sensitize DDP-resistant gastric cancer cell lines to DDP (Gu et al, 2020).…”