Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Xu, Xuefeng; Dai, Huaping; Geng, Jing; Wan, Xin; Huang, Xiaoxi; Li, Fēi; Jiang, Dianhua; Wang, Chen

doi:10.1038/labinvest.2015.68

Cited by 24 publications

(22 citation statements)

References 42 publications

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“…29,30 Earlier studies have shown that rapamycin increased CTGF expression via TGF-b signaling pathway in lung epithelial cells and lung fibroblasts. 28,35 These studies also support our finding that CTGF may play a role in CF lung fibrosis through elevated miR-155 expression and consequent suppression of RPTOR levels.…”

Section: Discussionsupporting

confidence: 82%

“…It has been shown that rapamycin treatment increased CTGF through TGF-b, but independent of SMAD phosphorylation through the PI3K/Akt pathway. 35 Our study only examined how phosphorylation of SMAD2 is induced through activation of TGF-b, resulting in increased expression of CTGF in CF lung epithelial cells. Our previous report demonstrated that PI3K/Akt pathway is activated in CF through elevated expression of miR-155; therefore, it is also possible that these mechanisms together are contributing to the fibrotic phenotype of CF lung disease.…”

Section: Discussionmentioning

confidence: 99%

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RPTOR, a novel target of miR-155, elicits a fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF

et al. 2016

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(2016) RPTOR, a novel target of miR-155, elicits a fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF, RNA Biology, 13:9, 837-847, DOI: 10.1080/15476286.2016 ABSTRACTCystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the most frequent of which is F508del-CFTR. CF is characterized by excessive secretion of pro-inflammatory mediators into the airway lumen, inducing a highly inflammatory cellular phenotype. This process triggers fibrosis, causing airway destruction and leading to high morbidity and mortality. We previously reported that miR-155 is upregulated in CF lung epithelial cells, but the molecular mechanisms by which miR-155 affects the disease phenotype is not understood. Here we report that RPTOR (regulatory associated protein of mTOR, complex 1) is a novel target of miR-155 in CF lung epithelial cells. The suppression of RPTOR expression and subsequent activation of TGF-b signaling resulted in the induction of fibrosis by elevating connective tissue growth factor (CTGF) abundance in CF lung epithelial cells. Thus, we propose that miR-155 might regulate fibrosis of CF lungs through the increased CTGF expression, highlighting its potential value in CF therapy.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

RPTOR, a novel target of miR-155, elicits a fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF

et al. 2016

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“…31, 32, 33 Among these multiple molecules, TGF- β was reported to act upstream and synergize with action of the CTGF in cellular functions. 14, 15, 16 To this end, we hypothesized whether TGF- β signal was activated in the process of TMZ-induced CTGF upregulation during GB chemotherapy.…”

Section: Resultsmentioning

confidence: 99%

Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling

Zeng¹,

Zhao²,

Xu³

et al. 2017

Cell Death Dis

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Limited benefits and clinical utility of temozolomide (TMZ) for glioblastoma (GB) are frequently compromised by the development of acquired drug resistance. Overcoming TMZ resistance and uncovering the underlying mechanisms are challenges faced during GB chemotherapy. In this study, we reported that connective tissue growth factor (CTGF) was associated with GB chemoresistance and significantly upregulated in TMZ-treated GB cells. CTGF knockdown promoted TMZ-induced cell apoptosis and enhanced chemosensitivity, whereas its overexpression markedly conferred TMZ resistance in vitro and in vivo. Moreover, CTGF promoted TMZ resistance through stem-like properties acquisition and CD44 interference reversed the CTGF-induced TMZ resistance. Mechanistically, further investigation revealed that the TMZ-induced CTGF upregulation was tissue growth factor (TGF-β) dependent, and regulated by TGF-β1 activation through Smad and ERK1/2 signaling. Together, our results suggest a pivotal role of CTGF-mediated TMZ resistance through TGF-β1-dependent activation of Smad/ERK signaling pathways. These data provide us insights for identifying potential targets that are beneficial for overcoming TMZ resistance in GB.

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“…Phosphoinositide 3-kinase (PI3K) was reported as a promising therapeutic target for idiopathic pulmonary fibrosis (23). Rapamycin may increase connective tissue growth factor expression in lung fibroblasts by regulating the PI3K signaling pathway (24). However, the association between the Wnt and PI3K/mitogen-activated protein kinase signaling pathways requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

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 increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Cited by 24 publications

References 42 publications

RPTOR, a novel target of miR-155, elicits a fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF

RPTOR, a novel target of miR-155, elicits a fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF

Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling

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

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