Metformin and LW6 impairs pancreatic cancer cells and reduces nuclear localization of YAP1

Zhang, Xianbin; Liu, Peng; Shang, Yongpeng; Kerndl, Hagen; Kumstel, Simone; Gong, Peng; Vollmar, Brigitte; Zechner, Dietmar

doi:10.7150/jca.33029

Cited by 12 publications

(9 citation statements)

References 51 publications

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“…3 Our overall analysis showed that diabetic patients with metformin use had a significantly reduced risk of HCC (relative risk 0.24, 95% confidence interval 0.13-0.46). These results were supported by experimental studies and multiple potential anti-cancer mechanisms of metformin were proposed, 3,[8][9][10] including inhibition of cell proliferation and hepatic gluconeogenesis, activation of AMPK, and modulation of microRNAs expression.…”

Section: Introductionmentioning

confidence: 62%

“…3 Epidemiological studies have demonstrated that treatment with metformin can reduce the risk of some cancers, such as HCC, breast cancer, colorectal cancer and pancreatic cancer. [8][9][10] For the association of metformin use with HCC risk, we have published one meta-analysis which included seven studies and 16,549 diabetic patients. 3 Our overall analysis showed that diabetic patients with metformin use had a significantly reduced risk of HCC (relative risk 0.24, 95% confidence interval 0.13-0.46).…”

Section: Introductionmentioning

confidence: 99%

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<p>Metformin Induces Autophagy via the AMPK-mTOR Signaling Pathway in Human Hepatocellular Carcinoma Cells</p>

Gao¹,

Long²,

Zhang³

et al. 2020

CMAR

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Background Metformin may exert the anticancer effect on multiple types of cancers and some potential mechanisms have been suggested. Our study was designed to determine the effect of metformin on the cell autophagy and autophagic flux via the AMPK-mTOR signaling pathway in human hepatocellular carcinoma (HCC) cells. Methods MHCC97H and HepG2 cell lines were cultured and treated without and with metformin at various concentrations (2, 5, 10 and 20 mM) for 48 h. Then, 10 mM was determined as the optimal concentration and the HCC cells were treated with metformin for 12, 24, 48, and 72 h. MTT assay was used to assess the cell viability and Western blotting was used to determine the expression of proteins (LC3-II, p62, phospho-AMPKα, phospho-mTOR, mTOR, phospho-p70 S6 Kinase, p70 S6 Kinase, PARP1, Caspase-9 and Caspase-3). Autophagy inhibitor 3-methyladenine, EGFP-LC3 and mCherry-GFP-LC3B plasmid transfection were used for further study. Results Metformin inhibited significantly the viability of MHCC97H and HepG2 cells in a dose- and time-dependent manner. For the apoptotic properties, activation of Caspase-9 and Caspase-3 and PARP cleavage were not observed after treatment with metformin. MHCC97H cells were transfected with a EGFP-LC3 plasmid and treatment with metformin could lead to the increased level of LC3-II and decreased level of p62. In metformin-induced autophagy, AMPK expression was activated, and the phosphorylation levels of mTOR and p70 S6 Kinase were inhibited. Metformin treatment and mCherry-GFP-LC3B plasmid transfection showed that metformin could induce the autophagic flux. 3-Methyladenine (3-MA) partly abolished this effect. Conclusion Metformin could induce the autophagy, autophagic flux, and activate the AMPK-mTOR signaling pathway in human HCC cells.

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Section: Introductionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

<p>Metformin Induces Autophagy via the AMPK-mTOR Signaling Pathway in Human Hepatocellular Carcinoma Cells</p>

Gao¹,

Long²,

Zhang³

et al. 2020

CMAR

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“…Consequently, the OXPHOS inhibitors could be used to target cancer cell metabolism in PAAD where OXPHOS is upregulated. Interestingly, recent observation revealed YAP1 was involved in the anti-cancer effect of OXPHOS inhibitors (metformin plus LW6) [ 36 ]. In the study, the authors demonstrated that metformin in combination with LW6 impaired pancreatic cancer cells and inhibited nuclear localization of YAP1 by phosphorylation of YAP1 at serine 127.…”

Section: Discussionmentioning

confidence: 99%

Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study

Tang

et al. 2021

Pathol. Oncol. Res.

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Background: Yes-associated protein 1 (YAP1) is the main downstream effector of the Hippo signaling pathway, which is involved in tumorigenesis. This study aimed to comprehensively understand the prognostic performances of YAP1 expression and its potential mechanism in pan-cancers by mining databases.Methods: The YAP1 expression was evaluated by the Oncomine database and GEPIA tool. The clinical significance of YAP1 expression was analyzed by the UALCAN, GEPIA, and DriverDBv3 database. Then, the co-expressed genes with YAP1 were screened by the LinkedOmics, and annotated by the Metascape and DAVID database. Additionally, by the MitoMiner 4.0 v tool, the YAP1 co-expressed genes were screened to obtain the YAP1-associated mitochondrial genes that were further enriched by DAVID and analyzed by MCODE for the hub genes.Results: YAP1 was differentially expressed in human cancers. Higher YAP1 expression was significantly associated with poorer overall survival and disease-free survival in adrenocortical carcinoma (ACC), brain Lower Grade Glioma (LGG), and pancreatic adenocarcinoma (PAAD). The LinkedOmics analysis revealed 923 co-expressed genes with YAP1 in adrenocortical carcinoma, LGG and PAAD. The 923 genes mainly participated in mitochondrial functions including mitochondrial gene expression and mitochondrial respiratory chain complex I assembly. Of the 923 genes, 112 mitochondrial genes were identified by MitoMiner 4.0 v and significantly enriched in oxidative phosphorylation. The MCODE analysis identified three hub genes including CHCHD1, IDH3G and NDUFAF5.Conclusion: Our findings showed that the YAP1 overexpression could be a biomarker for poor prognosis in ACC, LGG and PAAD. Specifically, the YAP1 co-expression genes were mainly involved in the regulation of mitochondrial function especially in oxidative phosphorylation. Thus, our findings provided evidence of the carcinogenesis of YAP1 in human cancers and new insights into the mechanisms underlying the role of YAP1 in mitochondrial dysregulation.

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“…PAAD is the most aggressive and fatal tumor [ 20 , 21 ]. Due to the lack of a sensitive and specific test of PAAD, the tumors have already spread from the pancreas to the liver and lung [ 22 ]. Thus, it needs to develop a novel test that can diagnose PAAD at an early stage and monitor the treatment response.…”

Section: Discussionmentioning

confidence: 99%

Development of a Transcription Factor-Based Prognostic Model for Predicting the Immune Status and Outcome in Pancreatic Adenocarcinoma

Zhang

Liu

et al. 2022

Journal of Immunology Research

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Pancreatic adenocarcinoma (PAAD) is the most common primary malignancy of the pancreas. Growing studies indicate that transcription factors (TFs) are abnormally expressed in PAAD. We, therefore, aimed to evaluate the effect of TFs in PAAD and develop a TF-based prognostic signature for the patients. The expression of the TFs and the clinical characteristics were obtained from TCGA datasets. The levels of the TFs were evaluated in PAAD tissues or nontumor tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to determine the potential function of the dysregulated TFs. To create a prognostic signature, we used univariate and multivariate Cox regression. In addition, the relationship between risk score and tumor microenvironment was analyzed. In this study, we observed 19 increased and 10 decreased TFs in PAAD tissues. KEGG assays indicated that dysregulated TFs were involved in transcriptional misregulation in cancer. Multivariate Cox analysis identified two prognostic factors, Zinc finger protein 488 and BCL11A; and we developed a risk score model by these two factors. The Kaplan-Meier estimator suggested that patients with high risk exhibited a shorter overall survival than those with low risk. The receiver operating characteristic curve proved that the accuracy of this prognostic signature was 0.686 in predicting the 5-year survival. In addition, we observed that the high score was distinctly related to advanced tumor stage and immune infiltrates. Taken together, we developed a novel TF-related model which could be applied as a potential prognostic tool for PAAD and may guide the choice of immunotherapies.

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Metformin and LW6 impairs pancreatic cancer cells and reduces nuclear localization of YAP1

Cited by 12 publications

References 51 publications

<p>Metformin Induces Autophagy via the AMPK-mTOR Signaling Pathway in Human Hepatocellular Carcinoma Cells</p>

<p>Metformin Induces Autophagy via the AMPK-mTOR Signaling Pathway in Human Hepatocellular Carcinoma Cells</p>

Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study

Development of a Transcription Factor-Based Prognostic Model for Predicting the Immune Status and Outcome in Pancreatic Adenocarcinoma

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