Triptolide interrupts rRNA synthesis and induces the RPL23‑MDM2‑p53 pathway to repress lung cancer cells

2020

Medicine

This is a study on the potential therapeutic targets and pharmacological mechanism of Tripterygium wilfordii (TW) in acute myeloid leukemia (AML) based on network pharmacology. Active components of TW were obtained by network pharmacology through oral bioavailability, drug-likeness filtration. Comparative analysis was used to investigate the overlapping genes between active ingredient's targets and AML treatment-related targets. Using STRING database to analyze interactions among overlapping genes. Both KEGG pathway analysis and Gene Ontology enrichment analysis were conducted in DAVID. These genes were analyzed for survival in OncoLnc database. We screened 53 active ingredients; the results of comparative analysis showed that 8 active ingredients had an effect on AML treatment. On the basis of the active ingredients and overlapping genes, we constructed the Drug-Compounds-Genes-Disease Network. Survival analysis of overlapping genes indicated that some targets possessed a significant influence on patients’ survival and prognosis. The enrichment analysis showed that the main pathways of targets were Toll-like receptor signaling pathway, NF-kappa B signaling pathway, and HIF-1 signaling pathway. This study, using a network pharmacologic approach, provides another strategy that can help us to understand the mechanisms by which TW treats AML comprehensively.

Section: Discussionmentioning

confidence: 99%

Network pharmacology-based strategy for predicting therapy targets of Tripterygium wilfordii on acute myeloid leukemia

Fang

2020

Medicine

“…The results show that some of these genes have a signi cant impact on the survival and prognosis of patients. And some genes have been experimentally proven to be the target of TW treatment of diseases such as AR, CD14, BCL2 (39)(40)(41) . This means that these genes may be the crucial target of TW in the treatment of leukemia.…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-Based Strategy for Predicting Therapy Targets of Tripterygium wilfordii on Acute Myeloid Leukemia

Fang

Chen

2020

Preprint

Background. Acute myeloid leukemia (AML) is a common malignant tumor of the hematopoietic system. How to extend the survival time of AML patients and improve their prognosis is still a major medical problem. Chinese medicine has a long history in treating AML. Tripterygium wilfordii (TW) is a traditional Chinese medicine. With the deepening of pharmacological research of traditional Chinese medicine, triptolide, one of its active ingredients, has been proven to have a positive effect on the treatment of AML. Therefore，this study aimed on studying the potential therapeutic targets and pharmacological mechanism of TW in Acute myeloid leukemia (AML) based on network pharmacology.Methods. The active components of TW were obtained by network pharmacology through oral bioavailability, drug-likeness filtration. Comparative analysis was used to study the overlapping genes between active ingredient’s targets and AML treatment-related targets. Using STRING database to analyze interactions between overlapping genes. KEGG pathway analysis and Gene Ontology enrichment analysis were conducted in DAVID. These genes were analyzed for survival in OncoLnc database.Key findings. We screened 53 active ingredients, the results of comparative analysis showed that 8 active ingredients had an effect on AML treatment. Based on the active ingredients and overlapping genes, we constructed the Drug-Compounds-Genes-Disease Network. Survival analysis of overlapping genes indicated that some targets possess a significant influence on patients’ survival and prognosis. The enrichment analysis showed that the main pathways of targets are Toll-like receptor signaling pathway, NF-kappa B signaling pathway and HIF-1 signaling pathway.Conclusion. This study, using a network pharmacologic approach, provides another strategy that can help us to understand the mechanisms by which TW treats AML comprehensively.

“…When cancer cells undergo uncontrolled growth and proliferation, they increase the biosynthesis of ribosomal biogenesis and the production of RPs. Growing evidence suggests the existence of an association between RPL23 expression and tumor invasiveness and aggressiveness (64,65,76). Indeed, RPL23 was reported to be up-regulated in human prostate cancer, lung cancer, and hepatocellular carcinoma (66,77,78).…”

Section: Discussionmentioning

confidence: 99%

Novel insights into the mechanisms by which lncRNAHOTAIR regulates migration and invasion in HeLa cells

Zheng

Fan³

et al. 2020

Preprint

Background HOTAIR, as one of the few well-studied oncogenic lncRNAs, is involved in human tumorigenesis and is dysregulated in most human cancers. The transcription co-activator factor YAP1 is broadly expressed in many tissues, and promotes cancer metastasis and progression. However, the precise biological roles of HOTAIR and YAP1 in cancer cells remain unclear. Methods The expression levels of HOTAIR and YAP1 were measured by quantitative PCR (qPCR), immunoblotting. Wound-healing and transwell assays were used to examine the invasive abilities of HeLa cells. Luciferase reporter assays and CHIP were used to determine how YAP1 regulates RPL23. A xenograft mouse mode was used to assess the correlation between HOTAIR and YAP1 in vivo. Result In this study, we showed that HOTAIR regulates H3K27 histone modification in the promoter of miR-200a to mediate miR-200a expression byrecruiting EZH2. YAP1, as a potential target gene of miR-200a, aggravated the effects of miR-200a on the migration and invasion of HeLa cells. YAP1 activated the transcription of RPL23, which is a novel target of YAP1 transcriptional regulation. Agreement with this, the expression of YAP1 and RPL23 was dramatically decreased after injecting HeLa cells transfected with siHOTAIR in a xenograft mouse model. Conclusion These elucidates that HOTAIR, as an oncogenic lncRNA, recruits EZH2 to reduce miR-200a-3p expression via H3k27 trimethylation in the miR-200a-3p promoter. As a target gene of miR-200a-3p,YAP1 then promotes the migration and invasion of HeLa cells by mediating the downstream transcription of RPL23 which normally functions as a cancer-promoting factor. Accordingly, we propose a novel model of the molecular mechanism by which HOTAIR promotes the migration and invasion of cancer cells involving the miR-200a-3p/YAP1/RPL23 axis.