GDC-0349 inhibits non-small cell lung cancer cell growth

Han, Yang; Zhao, Jun; Zhao, Min; Li, Zhao; Zhou, Li-Na; Duan, Yuxia; Li, Gang

doi:10.1038/s41419-020-03146-w

Cited by 17 publications

(19 citation statements)

References 60 publications

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“…It is also associated with apoptosis inhibition and therapy-resistance, and represents as an important therapeutic target of NSCLC [ 5 , 38 – 41 ]. Targeted inhibition of mTOR cascade, on the other hand, could produce significant anti-tumor activity in NSCLC cells [ 29 , 38 , 41 , 42 ]. Bonekamp et al found that POLRMT inhibition by small molecular inhibitors could result in robust inhibition of S6 phosphorylation [ 15 ], a key indicator of mTORC1 activation.…”

Section: Discussionmentioning

confidence: 99%

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The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth

et al. 2021

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POLRMT (RNA polymerase mitochondrial) is responsible for the transcription of mitochondrial genome encoding key components of oxidative phosphorylation. This process is important for cancer cell growth. The current study tested expression and potential functions of POLRMT in non-small cell lung cancer (NSCLC). TCGA cohorts and the results from the local lung cancer tissues showed that POLRMT is overexpressed in human lung cancer tissues. In both primary human NSCLC cells and A549 cells, POLRMT silencing (by targeted lentiviral shRNAs) or knockout (through CRSIPR/Cas9 gene editing method) potently inhibited cell viability, proliferation, migration, and invasion, and induced apoptosis activation. On the contrast, ectopic overexpression of POLRMT using a lentiviral construct accelerated cell proliferation and migration in NSCLC cells. The mtDNA contents, mRNA levels of mitochondrial transcripts, and subunits of respiratory chain complexes, as well as S6 phosphorylation, were decreased in POLRMT-silenced or -knockout NSCLC cells, but increased after ectopic POLRMT overexpression. In vivo, intratumoral injection of POLRMT shRNA adeno-associated virus (AAV) potently inhibited NSCLC xenograft growth in severe combined immune deficiency mice. The mtDNA contents, mRNA levels of mitochondria respiratory chain complex subunits, and S6 phosphorylation were decreased in POLRMT shRNA AAV-injected NSCLC xenograft tissues. These results show that POLRMT is a novel and important oncogene required for NSCLC cell growth in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

“…A549 cell line was from Dr Li at Wenzhou Medical University [ 28 , 29 ] and cells was cultivated in RPMI-1640 medium containing 8% FBS in a humidified atmosphere containing 5% CO 2 . Using the described protocols [ 30 , 31 ], the primary human NSCLC cells were derived from three different patients, pNSCLC1, pNSCLC2, and pNSCLC3.…”

Section: Methodsmentioning

confidence: 99%

The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth

et al. 2021

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“…mTOR acts in a synergistic manner to inhibit tumor growth in mouse prostate and lung cancer models, and phosphorylated or activated mTOR is found in 74% of the NSCLCs, making it an additional target for NSCLC therapy ( Marinov et al, 2007 ). In A549 and primary human NSCLC cells, GDC-0349 inhibits NSCLC cell growth, proliferation, cell cycle progression, migration, and invasion through the Akt-Akt-mTOR pathway, while inducing significant apoptotic activation ( Yang et al, 2020 ). Analysis of a receiver operating characteristic curve (area under curve = 0.6785) showed that the expression of MCL-1 is an important critical value for predicting prognosis in 30.0% of the NSCLC tumor cell types.…”

Section: Discussionmentioning

confidence: 99%

Using Network Pharmacology and Molecular Docking to Explore the Mechanism of Shan Ci Gu (Cremastra appendiculata) Against Non-Small Cell Lung Cancer

et al. 2021

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Background: In recent years, the incidence and mortality rates of non-small cell lung cancer (NSCLC) have increased significantly. Shan Ci Gu is commonly used as an anticancer drug in traditional Chinese medicine; however, its specific mechanism against NSCLC has not yet been elucidated. Here, the mechanism was clarified through network pharmacology and molecular docking.Methods: The Traditional Chinese Medicine Systems Pharmacology database was searched for the active ingredients of Shan Ci Gu, and the relevant targets in the Swiss Target Prediction database were obtained according to the structure of the active ingredients. GeneCards were searched for NSCLC-related disease targets. We obtained the cross-target using VENNY to obtain the core targets. The core targets were imported into the Search Tool for the Retrieval of Interacting Genes/Proteins database, and Cytoscape software was used to operate a mesh chart. R software was used to analyze the Gene Ontology biological processes (BPs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The core targets and active compounds were molecularly docked through Auto-Dock Vina software to predict the detailed molecular mechanism of Shan Ci Gu for NSCLC treatment. We did a simple survival analysis with hub gene to assess the prognosis of NSCLC patients.Results: Three compounds were screened to obtain 143 target genes and 1,226 targets related to NSCLC, of which 56 genes were related to NSCLC treatment. Shan Ci Gu treatment for NSCLC involved many BPs and acted on main targets including epidermal growth factor receptor (EGFR), ESR1, and SRC through signaling pathways including the endocrine resistance, EGFR tyrosine kinase inhibitor resistance, and ErbB signaling pathways. Shan Ci Gu might be beneficial for treating NSCLC by inhibiting cell proliferation and migration. Molecular docking revealed that the active compounds β-sitosterol, stigmasterol, and 2-methoxy-9,10-dihydrophenanthrene-4,5-diol had good affinity with the core target genes (EGFR, SRC, and ESR1). Core targets included EGFR, SRC, ESR1, ERBB2, MTOR, MCL1, matrix metalloproteinase 2 (MMP2), MMP9, KDR, and JAK2. Key KEGG pathways included endocrine resistance, EGFR tyrosine kinase inhibitor resistance, ErbB signaling, PI3K-Akt signaling, and Rap1 signaling pathways. These core targets and pathways have an inhibitory effect on the proliferation of NSCLC cells.Conclusion: Shan Ci Gu can treat NSCLC through a multi-target, multi-pathway molecular mechanism and effectively improve NSCLC prognosis. This study could serve as a reference for further mechanistic research on wider application of Shan Ci Gu for NSCLC treatment.

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“…A recombinant adenoviral construct encoding the constitutively-active Akt1 (caAkt1, S473D) was provided by Dr. Li at Wenzhou Medical University ( 26 , 27 ), and was transduced to pNSCLC-1 cells. Cells with GFP were then sorted by FACS and monoclonal single cells were distributed into 192-well plates.…”

Section: Methodsmentioning

confidence: 99%

The Anti-Non-Small Cell Lung Cancer Cell Activity by a mTOR Kinase Inhibitor PQR620

Zha

Xia

et al. 2021

Front. Oncol.

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In non-small-cell lung carcinoma (NSCLC), aberrant activation of mammalian target of rapamycin (mTOR) contributes to tumorigenesis and cancer progression. PQR620 is a novel and highly-potent mTOR kinase inhibitor. We here tested its potential activity in NSCLC cells. In primary human NSCLC cells and established cell lines (A549 and NCI-H1944), PQR620 inhibited cell growth, proliferation, and cell cycle progression, as well as cell migration and invasion, while inducing significant apoptosis activation. PQR620 disrupted assembles of mTOR complex 1 (mTOR-Raptor) and mTOR complex 2 (mTOR-Rictor-Sin1), and blocked Akt, S6K1, and S6 phosphorylations in NSCLC cells. Restoring Akt-mTOR activation by a constitutively-active Akt1 (S473D) only partially inhibited PQR620-induced cytotoxicity in NSCLC cells. PQR620 was yet cytotoxic in Akt1/2-silenced NSCLC cells, supporting the existence of Akt-mTOR-independent mechanisms. Indeed, PQR620 induced sphingosine kinase 1 (SphK1) inhibition, ceramide production and oxidative stress in primary NSCLC cells. In vivo studies demonstrated that daily oral administration of a single dose of PQR620 potently inhibited primary NSCLC xenograft growth in severe combined immune deficient mice. In PQR620-treated xenograft tissues, Akt-mTOR inactivation, apoptosis induction, SphK1 inhibition and oxidative stress were detected. In conclusion, PQR620 exerted potent anti-NSCLC cell activity via mTOR-dependent and -independent mechanisms.

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GDC-0349 inhibits non-small cell lung cancer cell growth

Cited by 17 publications

References 60 publications

The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth

The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth

Using Network Pharmacology and Molecular Docking to Explore the Mechanism of Shan Ci Gu (Cremastra appendiculata) Against Non-Small Cell Lung Cancer

The Anti-Non-Small Cell Lung Cancer Cell Activity by a mTOR Kinase Inhibitor PQR620

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