Triptolide inhibits pancreatic cancer cell proliferation and migration via down-regulating PLAU based on network pharmacology of Tripterygium wilfordii Hook F

Zhao, Xin; Liu, Zhe; Ren, Zhiwei; Wang, Huaguang; Wang, Zisong; Zhai, Jialei; Cao, Di; Lyu, Shaocheng; Li, Lixin; Lang, Ren; He, Qiang

doi:10.1016/j.ejphar.2020.173225

Cited by 40 publications

(33 citation statements)

References 39 publications

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“…PLAU can increase cell proliferation through the activate growth factors or adhesion molecules, for example, VEGF, TGF-β and the α5β1 integrins ( Aguirre-Ghiso et al, 2001 ; Duffy, 2004 ; Ulisse et al, 2009 ). PLAU could increase cell adhesion and migration during metastasis and proliferation of tumor cells ( Zhao et al, 2020b ), which may explain our finding that elevated expression of PLAU in node metastasis tumors. Under hypoxia conditions, PLAU expression can activate downstream Akt and Rac1 signaling pathways, thus promoting EMT and cell invasion ( Lester et al, 2007 ).…”

Section: Discussionmentioning

confidence: 67%

Overexpressed PLAU and its potential prognostic value in head and neck squamous cell carcinoma

Chen

Wang

et al. 2021

PeerJ

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Background Metastasis is a major event for survival and prognosis in patients with head and neck squamous cell carcinomas (HNSCC). A primary cause of metastasis is the proteolytic degradation of the extracellular matrix (ECM). The plasminogen activator urokinase (PLAU) is involved in the transformation of plasminogen to plasmin leading to hydrolyzation of ECM-related proteins. However, the role of PLAU expression in HNSCC is unclear and the worth being investigated. Methods PLAU expression profiles and clinical parameters from multiple HNSCC datasets were used to investigate the relationship of PLAU expression and HNSCC survival. GO and PPI network were established on PLAU-related downstream molecular. The stroma score was deconvoluted for analysis of PLAU’s association with the immune environment. ROC analysis was applied to show the performance of PLAU in predicting HNSCC prognosis. Results PLAU mRNA was significantly elevated, as opposed to its methylation, in HNSCC tumor samples over normal specimens (all p < 0.01). Univariate and multivariate cox analysis showed PLAU could be an independent indicator for HNSCC prognosis. Combining with neck lymph node status, the AUC of PLAU in predicting 5-years overall survival reached to 0.862. GO enrichment analysis showed the major biological process (extracellular matrix organization and the P13K-Akt signaling pathway) may involve to the possible mechanism of PLAU’s function on HNSCC prognosis. Furthermore, PLAU expression was positively correlated with stroma cell score, M1 type macrophages, and negatively associated with CD4 + T cell, Tregs cell, and follicular helper T cell. Conclusions PLAU might be an independent biomarker for predicting outcomes of HNSCC patients. The elevated expression of PLAU was associated with HPV positivity and neck node status. The PI3K-Akt pathway and aberrant proportions of immune cells might underly the mechanism of PLAU’s oncogene role in HNSCC.

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Section: Discussionmentioning

confidence: 67%

Overexpressed PLAU and its potential prognostic value in head and neck squamous cell carcinoma

Chen

Wang

et al. 2021

PeerJ

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“…4c, d). This was somewhat expected and used as a control since TPL only inhibits the ATPase activity of XPB but does not affect its expression levels 20 .…”

Section: Se-associated Genes Are Downregulated By Tpl At the Protein mentioning

confidence: 99%

“…Triptolide (TPL), a natural compound isolated from the Chinese herb Tripterygium wilfordii (Thunder God vine), has shown promising preclinical antitumor activity against a number of cancers 15 – 17 including pancreatic cancer 18 – 20 . The water-soluble pro-drug of triptolide, Minnelide, was recently reported to show promising activity in patients with gastrointestinal malignancies in Phase I clinical trial 21 , 22 .…”

Section: Introductionmentioning

confidence: 99%

Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts

Noel

Hussein

et al. 2020

Oncogenesis

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The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous, fibrotic, and hypovascular, marked by extensive desmoplasia and maintained by the tumor cells, cancer-associated fibroblasts (CAFs) and other stromal cells. There is an urgent need to identify and develop treatment strategies that not only target the tumor cells but can also modulate the stromal cells. A growing number of studies implicate the role of regulatory DNA elements called super-enhancers (SE) in maintaining cell-type-specific gene expression networks in both normal and cancer cells. Using chromatin activation marks, we first mapped SE networks in pancreatic CAFs and epithelial tumor cells and found them to have distinct SE profiles. Next, we explored the role of triptolide (TPL), a natural compound with antitumor activity, in the context of modulating cell-type-specific SE signatures in PDAC. We found that TPL, cytotoxic to both pancreatic tumor cells and CAFs, disrupted SEs in a manner that resulted in the downregulation of SE-associated genes (e.g., BRD4, MYC, RNA Pol II, and Collagen 1) in both cell types at mRNA and protein levels. Our observations suggest that TPL acts as a SE interactive agent and may elicit its antitumor activity through SE disruption to re-program cellular cross talk and signaling in PDAC. Based on our findings, epigenetic reprogramming of transcriptional regulation using SE modulating compounds such as TPL may provide means for effective treatment options for pancreatic cancer patients.

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“…Low-expression of PLAU prohibited proliferation and migration of PC cells. 37 Moreover, the expression of CD1D, ERAP2, SSTR1, CXCL9, CXCL11, IL1A, EREG also certainly influenced the development of PC. [38][39][40][41][42][43][44][45][46] Hence, these studies demonstrated the correlation between our IRGPs signature with the progression of PC.…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of PLAU was correlated with lymph node metastasis and poor prognosis of PC. Low‐expression of PLAU prohibited proliferation and migration of PC cells 37 . Moreover, the expression of CD1D, ERAP2, SSTR1, CXCL9, CXCL11, IL1A, EREG also certainly influenced the development of PC 38–46 .…”

Section: Discussionmentioning

confidence: 99%

A signature of 18 immune‐related gene pairs to predict the prognosis of pancreatic cancer patients

Zhu

Wu³

et al. 2020

Immunity Inflam & Disease

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Pancreatic cancer is one of the most lethal malignancies. With the promising prospects conveyed by immunotherapy in cancers, we aimed to construct an immune‐related gene pairs (IRGPs) signature to predict the prognosis of pancreatic cancer patients. We downloaded clinical and transcriptional data of pancreatic cancer patients from The Cancer Genome Atlas data set as the training group and GSE57495 data set as the verification group. We filtered immune‐related transcriptional data by IMMPORT. With the assistance of lasso penalized Cox regression, we constructed our prognostic IRGPs signature and divided all samples into high‐/low‐risk groups by receiver operating characteristic curve for further comparisons. The comparisons between high‐ and low‐risk groups including survival rate, multivariate, and univariate Cox proportional‐hazards analysis, infiltration of immune cells, and Gene Set Enrichment Analysis (GSEA). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) are facilitated to analyze the proceedings in which our IRGPs signature may involve in. The results revealed that 18 IRGPs were defined as our prognostic signature. The prognostic value of this IRGPs signature was verified from the GSE57495 data set. We further demonstrated the independent prognostic value of this IRGPs signature. The contents of six immune cells between high‐/low‐risk groups were different, which was associated with the progression of diverse cancers. Results from GO, KEGG, and GSEA revealed that this IRGPs signature was involved in extracellular space, immune response, cancer pathways, cation channel, and gated channel activities. Evidently, this IRGPs signature will provide remarkable value for the therapy of pancreatic cancer patients.

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Triptolide inhibits pancreatic cancer cell proliferation and migration via down-regulating PLAU based on network pharmacology of Tripterygium wilfordii Hook F

Cited by 40 publications

References 39 publications

Overexpressed PLAU and its potential prognostic value in head and neck squamous cell carcinoma

Overexpressed PLAU and its potential prognostic value in head and neck squamous cell carcinoma

Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts

A signature of 18 immune‐related gene pairs to predict the prognosis of pancreatic cancer patients

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