Targeting PI3K/mTOR Signaling in Cancer

Porta, Camillo; Paglino, Chiara; Mosca, Alessandra

doi:10.3389/fonc.2014.00084

Cited by 467 publications

(8 citation statements)

References 81 publications

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“…We also investigated the impact of lncRNA OGFRP1 downregulation on AKT/mTOR signaling pathway, which was reported to regulate numerous biological processes in tumor, such as cell proliferation and protein synthesis. 45 It was suggested that the phosphorylation levels of AKT and mTOR were significantly decreased in the siOGFRP1 group, which confirmed an inactivation status of AKT/mTOR signaling pathway. However, we could not confirm the protumor function of lncRNA OGFRP1 in another HCC cell line called HepG2, which demonstrated the high specificity of lncRNA functions and the complexity of tumor intracellular environment.…”

Section: Discussionmentioning

confidence: 85%

Downregulation of lncRNA OGFRP1 inhibits hepatocellular carcinoma progression by AKT/mTOR and Wnt/β-catenin signaling pathways

Chen¹,

You²,

Zheng³

et al. 2018

CMAR

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IntroductionIncreasing evidence demonstrates that long noncoding RNAs (lncRNAs) play important roles in the progression of hepatocellular carcinoma (HCC) by regulating gene expression. However, the identification of functional lncRNAs in HCC remains insufficient. Our study aimed to investigate the function of lncRNA OGFRP1, which has not been functionally researched before, in Hep3B and HepG2 cells.MethodslncRNA OGFRP1 in HCC cells was down-regulated by using RNAi technology. Quantitative real-time polymerase chain reaction was used to determine the mRNA expression of lncRNA OGFRP1. Cell proliferation was examined by CCK8 and clone formation assays. Cell cycle and apoptosis were analyzed by flow cytometry. Cell migration and invasion were assessed by using Scratch assay and transwell assay, respectively. Protein expression of signaling pathways was determined by using Western blot.ResultsCell proliferation of Hep3B was significantly inhibited by down-regulation of lncRNA OGFRP1 (P<0.05). Moreover, siOGFRP1 transfection induced Hep3B cell cycle arrest and apoptosis by regulating the expression of related proteins. Cell migration and invasion of Hep3B were also significantly inhibited by down-regulation of lncRNA OGFRP1. Wnt/β-catenin signaling pathway, involved in epithelial–mesenchymal transition (EMT), was inactivated by lncRNA OGFRP1 downregulation, including decreased expression of Wnt3a, β-catenin, N-cadherin and vimentin and increased expression of E-cadherin. We also found that the inhibitory effect of lncRNA OGFRP1 knockdown on Hep3B was mediated by the AKT/mTOR signaling pathway and IGF-1, an AKT signaling activator, could rescue the cellular phenotype. However, knockdown of lncRNA OGFRP1 did not influence cell proliferation, migration and invasion in HepG2 cells.ConclusionWe found that downregulation of lncRNA OGFRP1 suppressed the proliferation and EMT of HCC Hep3B cells through AKT and Wnt/β-catenin signaling pathways. However, lncRNA OGFRP1 exhibited a differentiated function in different HCC cell lines, which required further study in the future.

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Section: Discussionmentioning

confidence: 85%

Downregulation of lncRNA OGFRP1 inhibits hepatocellular carcinoma progression by AKT/mTOR and Wnt/β-catenin signaling pathways

Chen¹,

You²,

Zheng³

et al. 2018

CMAR

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“…The signaling pathway is reported to promote many cancer properties such as cell survival, growth, and proliferation. 25 , 26 …”

Section: Discussionmentioning

confidence: 99%

SIL1 functions as an oncogene in glioma by AKT/mTOR signaling pathway

Xu¹,

Xu²,

Zhang³

et al. 2018

OTT

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PurposeSIL1 is a ubiquitous protein localized to the endoplasmic reticulum and functions as a cochaperone of BiP. Previous studies have shown that function loss of SIL1 is often associated with neurological diseases, such as Marinesco-Sjögren Syndrome. However, no studies have investigated the function of SIL1 in tumors. In this study we aim to reveal functions of SIL1 and the underlying mechanisms in glioma.Materials and methodsFirst, by searching on Gene Expression Profiling Interactive Analysis, we examined SIL1 expression and prognostic value in glioblastoma multiforme (GBM) and brain lower grade glioma (LGG). Immunohistochemical analysis (IHC) was also performed to determine the endogenic SIL1 level. Cell counting kit-8 (CCK8) and clone formation assays were used to detect cell proliferation of U251 cells. Cell migration was detected by transwell assay and cell cycle and apoptosis were detected by flow cytometry. Western blot was performed to determine protein expression.ResultsWe found that the expression of SIL1 was increased by approximately 1.5-fold in GBM and 1.3-fold in LGG compared with normal controls (P<0.05) and negatively correlated with patients’ survival. IHC revealed that SIL1 expression was significantly higher in glioma tissues than that in paracancerous tissues (P<0.05). Glioma patients with high SIL1 expression accounted for 65.79% (25/38) of total samples and SIL1 expression significantly increased in grade IV glioma compared to grades I–III (P=0.026). Suppression of SIL1 expression led to significant inhibition of U251 cell proliferation. Transwell assay showed that cell migration of U251 was significantly inhibited by siSIL transfection, with an inhibitory rate reaching 69%. Flow cytometry detection showed that siSIL1 could induce apoptosis of U251 cells and upregulated the expression of the pro-apoptotic protein Bax and Caspase3-P17. However, siSIL1 transfection had no effect on the cell cycle. Mechanism studies demonstrated that siSIL1 transfection led to inactivation of AKT/mTOR signaling pathway, including decreased phosphorylation of AKT and mTOR without affecting protein expression, as well as decreased expression of the downstream effector p70S6K.ConclusionDownregulation of SIL1 inhibited the progression of glioma by suppressing the AKT/mTOR signaling pathway.

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“…PI3K plays a critical role in the development of acute and chronic tissue injury, including the process of tissue remodeling and emphysema [6]. PI3K/Akt pathway were found to be activated in cancers [1,3,4], closely associated with cancer proliferation. Down regulation of PI3K/Akt pathway may inhibit the migration and invasion of cancer cells such as NSCLC cells [7], acute promylocytic leukemia (APL) [8] and so on.…”

Section: Discussionmentioning

confidence: 99%

“…Given its prominent role in cancer, there is great interest in the development of inhibitors which are able to target several members of PI3K signaling pathway in clinical trials. These drug candidates include PI3K inhibitors, both pan-and isoformspecific inhibitors, AKT, mammalian target of rapamycin (mTOR), and dual PI3K/mTOR inhibitors [3,4]. The first group encompasses inhibitors able to bind all class I PI3Ks (pan inhibitors), and in particular PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ.…”

Section: Introductionmentioning

confidence: 99%

Effects of phosphoinositide 3-kinase inhibitor SHBM1009 on cancer cells proliferation

Wang

Huang

Shen

et al. 2018

MCT

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BACKGROUND: Phosphoinositide 3-kinase (PI3K) plays an important role in cellular proliferation and tumor progression. The objective of this study is to evaluate the potential mechanism and therapeutic effects of new PI3K inhibitor SHBM1009 on various cancer cells of digestive system on proliferation. METHODS: Six human hepatocellular carcinoma cell lines including 97H, 97L, A3, F11, MHCC-1, SMMC7721, one gastric cell line SGC-7901 and three primary testicular cancer TYST,TYST1,TYST2 cells were treated by 100ng/ml epidermal growth factor with or without 1uM NVP-BEZ-235 and SHBM1009 in Cell-IQ system in 24-well plates for 48h and up to 72h. The cell bio-behaviors, especially for cell proliferation of total cell number were measured by a real-time cell monitoring system, Cell-IQ continuous cell culturing platform. Images were captured at 30 min intervals. Cell-IQ system uses machine vision technology for monitoring and recording time-lapse data, and the cell functions and morphological parameters were quantified and analyzed. RESULTS: SHBM1009 could prevent EGF-induced cancer cells proliferation. Different patterns of inhibitory effects of SHBM1009 and NVP-BEZ-235, a dual PI3K/mechanistic target of rapamycin inhibitor, on EGF-induced cancer cells proliferation were observed. CONCLUSIONS: PI3K plays a critical role in the development of cancer progress, including proliferation, differentiation and anti-apoptosis. SHBM1009, a new PI3K inhibitor, could be new therapeutic alternatives for cancer treatment.

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Targeting PI3K/mTOR Signaling in Cancer

Cited by 467 publications

References 81 publications

Downregulation of lncRNA OGFRP1 inhibits hepatocellular carcinoma progression by AKT/mTOR and Wnt/β-catenin signaling pathways

Downregulation of lncRNA OGFRP1 inhibits hepatocellular carcinoma progression by AKT/mTOR and Wnt/β-catenin signaling pathways

SIL1 functions as an oncogene in glioma by AKT/mTOR signaling pathway

Effects of phosphoinositide 3-kinase inhibitor SHBM1009 on cancer cells proliferation

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Targeting PI3K/mTOR Signaling in Cancer

Cited by 467 publications

References 81 publications

Downregulation of lncRNA OGFRP1 inhibits hepatocellular carcinoma progression by AKT/mTOR and Wnt/&beta;-catenin signaling pathways

Downregulation of lncRNA OGFRP1 inhibits hepatocellular carcinoma progression by AKT/mTOR and Wnt/&beta;-catenin signaling pathways

SIL1 functions as an oncogene in glioma by AKT/mTOR signaling pathway

Effects of phosphoinositide 3-kinase inhibitor SHBM1009 on cancer cells proliferation

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Downregulation of lncRNA OGFRP1 inhibits hepatocellular carcinoma progression by AKT/mTOR and Wnt/β-catenin signaling pathways

Downregulation of lncRNA OGFRP1 inhibits hepatocellular carcinoma progression by AKT/mTOR and Wnt/β-catenin signaling pathways