Tripchlorolide induces autophagy in lung cancer cells by inhibiting the PI3K/AKT/mTOR pathway and improves cisplatin sensitivity in A549/DDP cells

Chen, Limin; Song, Tian-Jiao; Xiao, Jianlin; Huang, Zhenghui; Li, Yong; Lin, Tong

doi:10.18632/oncotarget.19201

Cited by 37 publications

(23 citation statements)

References 30 publications

(28 reference statements)

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“…Rapamycin is an inhibitor of mTOR and may activate autophagy (20,21). The present study revealed that rapamycin significantly inhibited PQ-induced EMT and the Wnt signaling pathway.…”

Section: Discussionsupporting

confidence: 53%

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

et al. 2018

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Abstract. Paraquat (PQ) is a herbicide that is widely used in developing countries, and pulmonary fibrosisis one of the most typical features of PQ poisoning. The molecular mechanism underlying PQ toxicity is largely unknown, which makes it difficult to treat. In the present study, western blot analysis, reverse transcription-quantitative polymerase chain reaction and fluorescent immunostaining were used to analyze the effects of rapamycin on PQ-induced epithelial-mesenchymal transition (EMT) in A549 and MRC-5 cells. It was revealed that rapamycin significantly downregulated the mesenchymal cell marker, α-smooth muscle actin, and significantly upregulated the epithelial cell marker, E-cadherin, at mRNA and protein expression levels compared with the PQ group. Treatment with PQ significantly increased Wnt1, low-density lipoprotein receptor-related protein (LRP)5, LRP6 and β-catenin expression levels in A549 cells, while rapamycin significantly inhibited these effects of PQ. Activation of the Wnt signaling pathway using lithium chloride attenuated the inhibitory effects of rapamycin on PQ-induced EMT. In conclusion, rapamycin protects against PQ-induced pulmonary EMT via the Wnt/β-catenin signaling pathway. IntroductionParaquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium) is a herbicide that is widely used in developing countries worldwide, which may cause severe toxicity in animals and humans (1). PQ poisoning was reported to account for up to a third of all suicides around the world (2). PQ poisoning may cause patients to develop acute multi-organ failure, pulmonary fibrosis and finally mortality due to respiratory failure (3). Pulmonary fibrosis is a typical feature of PQ poisoning, the onset of which may be several days or weeks following ingestion of PQ (4). Although PQ-induced pulmonary fibrosis has a high mortality rate, the molecular mechanisms underlying its toxicity are largely unknown, which makes it particularly hard to treat.Epithelial-mesenchymal transition (EMT) has been reported to be associated with pulmonary fibrosis following PQ exposure (3). It has also been reported that factors, including epithelial growth factor, transforming growth factor-β1 (TGF-β1), insulin-like growth factor and interleukin-17, may induce EMT (5). Myofibroblasts are key mediators in fibrosis. In murine models of hepatic and renal fibrosis, ~40% of α-smooth muscle actin (SMA)-positive myofibroblasts were derived from epithelial cells via EMT (6). However, to the best of our knowledge, the roles and mechanisms of rapamycin in the EMT process of A549 and MRC-5 cells remain unknown.In the present study, the roles and mechanisms of rapamycin on PQ-induced pulmonary fibrosis were investigated. It was revealed that rapamycin alleviated PQ-induced EMT in A549 and MRC-5 cells, and PQ activated the Wnt signaling pathway. Rapamycin inhibited the effects of PQ, and the activation of the Wnt signaling pathway attenuated the inhibitory effects of rapamycin on PQ-induced EMT. Materials and methodsReagents. PQ, rapamycin and lithium chloride (...

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“…Rapamycin is an inhibitor of mTOR and may activate autophagy (20,21). The present study revealed that rapamycin significantly inhibited PQ-induced EMT and the Wnt signaling pathway.…”

Section: Discussionsupporting

confidence: 53%

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

et al. 2018

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“…Documents demonstrated that autophagy contributes to cell survival and homeostasis by removing them is folded proteins and damaged organelles as well as intracellular pathogens through the lysosomal degradation pathway [16,39]. However, autophagy is a complicated pathway and activated by variety of factors, such as exposure to anoxia, starvation, chemical agents and radiation.…”

Section: Discussionmentioning

confidence: 99%

“…[15,16]. As the number of scientists investigating autophagy has increased, the complexity of autophagy has become increasingly dissected.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Alleviated the Symptoms of Fat Embolism Syndrome by Modulating Autophagy in a Rat Model

Zhang¹,

Zhang²,

Xu³

et al. 2017

Preprint

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As a high fatal disease, fat embolism syndrome is complication, which brought great pain to patient and their family served as a serious social burden. The mechanism of FES remains unclear. Autophagy controls the cell survival and homeostasis by removing the mis-folded proteins and damaged organelles as well as intracellular pathogens through a lysosomal degradation pathway. Increasing research documented that autophagy was wildly involved in variety of human diseases and had huge therapeutic potential. In our study, we first established the rat model of FES with the liquid fat by tail vein injection. We observed the up-regulated MPO expression and activity, increased Wet-to-Dry (W/D) lung weight, promoted quantity of fat granules, and the dominant disorder in the lung rat model of FES, compared to the control group. These observations demonstrated that we successfully build the rat model of FES. Then, we sought to dissect the role of the autophagy in the rat model of FES. The western blots analysis showed that the autophagy was inhibited in the rat model of FES constructed with liquid fat. Furthermore, Rapamycin could restore the repression of autophagy in rat model of FES. These investigations illustrated that autophagy was involved in FES. In addition, our experiments showed that Rapamycin could alleviate the symptoms of FES. Taken together, our study demonstrated the participation of autophagy in FES and further, as a potential therapeutic target, the modulation of autophagy could affect the symptom of rat model of FES.

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“…In our previous study, we found that T4 can increase the sensitivity of A549/DDP cells to cisplatin by decreasing the expression of MDR1. [15] Therefore, in this experiment, we decided to investigate the following: (1) whether AEG-1 affects the drug resistance of lung cancer cells, and (2) whether T4 can affect the expression of AEG-1 protein in lung cancer cells, and (3)whether T4 reduces cisplatin resistance by inhibiting AEG-1 gene expression in lung cancer cells. We clearly determined that AEG-1 protein is closely related to the drug resistance of lung cancer cells and found that T4 can in uence the expression of AEG-1 protein in lung cancer cells.…”

Section: Introductionmentioning

confidence: 99%

T4 Reduces Cisplatin Resistance by Inhibiting AEG-1 Gene Expression in Lung Cancer Cells

Song

Lin

Huang

et al. 2020

Preprint

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BackgroundLung cancer is one of the deadliest diseases in the world. Most lung cancer patients are resistant to chemotherapy drugs. In our study, we investigated whether T4 can reduce the resistance of lung cancer cells to chemotherapeutic drugs through the action of AEG-1.Materials and Methods1.A549 and A549/DDP cells were respectively transfected with overexpressing AEG-1 and knockdown AEG-1 plasmid. A549 and A549/DDP cells were added 0、25、50、100、200nM T4 respectively. 200nM T4 was selected for following experiments. A549/DDP cells were divided into A549/DDP empty group, T4 group, T4+AEG-1 overexpressing group. CCK8 assay was used to detect the proliferation of cells in each group. RT-qPCR and Western blotting were used to detect the expression of AEG-1 and MDR-1.ResultsAs expected, the expression of AEG-1 in A549 and A549/DDP cells is positively correlated with cisplatin resistance. When AEG-1 protein was overexpressed in A549 cells, the lethal effect of cisplatin on A549 cells was attenuated (all P<0.05). After AEG-1 protein was knocked down in A549/DDP cells, cisplatin was applied to the A549/DDP cells. The lethal effect was significantly increased compared to that in the control cells (all P<0.05). The expression of AEG-1 protein gradually decreased with increasing concentration of T4 in A549 and A549/DDP cells; The resistance to cisplatin was reduced after the addition of T4 to A549/DDP cells (P<0.05), and this effect was enhanced after transfection with the AEG-1 plasmid. ConclusionIn summary, T4 is important for increasing the sensitively of lung cancer cells to cisplatin. AEG-1 may be a key protein involved in this effect and may have an important impact on the survival rate of chemotherapy in patients with lung cancer in the future.

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Tripchlorolide induces autophagy in lung cancer cells by inhibiting the PI3K/AKT/mTOR pathway and improves cisplatin sensitivity in A549/DDP cells

Cited by 37 publications

References 30 publications

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

Rapamycin Alleviated the Symptoms of Fat Embolism Syndrome by Modulating Autophagy in a Rat Model

T4 Reduces Cisplatin Resistance by Inhibiting AEG-1 Gene Expression in Lung Cancer Cells

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