The 2-oxoglutarate analog 3-oxoglutarate decreases normoxic hypoxia-inducible factor-1α in cancer cells, induces cell death, and reduces tumor xenograft growth

Although cancer cells need more glucose than normal cells to maintain energy demand, chronic hyperglycemia induces metabolic alteration that may dysregulate signaling pathways, including the O-GlcNAcylation and HIF1A (Hypoxia-inducible factor 1-alpha) pathways. Metformin was demonstrated to evoke metabolic stress and induce cancer cell death. The aim of this study was to determine the cytotoxic efficiency of metformin on SKOV-3 cells cultured in hyperglycemia and normoglycemia. To identify the potential mechanism, we assessed the expression of O-linked β-N-acetlyglucosamine transferase (OGT) and glycoside hydrolase O-GlcNAcase (OGA), as well as hypoxia-inducible factor 1-alpha (HIF1A) and glucose transporters (GLUT1, GLUT3). SKOV-3 cells were cultured in normoglycaemia (NG, 5 mM) and hyperglycemia (HG, 25 mM) with and without 10 mM metformin for 24, 48, and 72 h. The proliferation rate, apoptotic and necrotic SKOV-3 cell death were evaluated. Real-Time qPCR was employed to determine mRNA expression of OGT, OGA, GLUT1, GLUT3, and HIF1A. Metformin significantly reduced the proliferation of SKOV-3 cells under normal glucose conditions. Whereas, the efficacy of metformin to induce SKOV-3 cell death was reduced in hyperglycemia. Both hyperglycemia and metformin induced changes in the expression of genes involved in the O-GlcNAcylation status and HIF1A pathway. The obtained results suggest that dysregulation of O-GlcNAcylation, and the related HIF1A pathway, via hyperglycemia, is responsible for the decreased cytotoxic efficiency of metformin in human ovarian cancer cells.

Download Full-text

Hypoxia-induced Fascin-1 upregulation is regulated by Akt/Rac1 axis and enhances malignant properties of liver cancer cells via mediating actin cytoskeleton rearrangement and Hippo/YAP activation

Cell Death Discovery ◽

10.1038/s41420-021-00778-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Jian Pu ◽

Youguan Huang ◽

Quan Fang ◽

Jianchu Wang ◽

Wenchuan Li ◽

...

Keyword(s):

Liver Cancer ◽

Actin Cytoskeleton ◽

Cancer Cells ◽

Potential Functions ◽

Tumor Xenograft ◽

Mesenchymal Transition ◽

Liver Cancer Cells ◽

Xenograft Growth ◽

Tumor Xenograft Growth ◽

Cytoskeleton Rearrangement

AbstractIn solid tumors, hypoxia facilitates malignant progression of cancer cells by triggering epithelial-mesenchymal transition (EMT) and cancer stemness. Fascin-1, an actin-bundling protein, takes part in the formation of many actin-based cellular structures. In the present study, we explored the potential functions of hypoxia-induced upregulation of Fascin-1 in liver cancer. Transcriptome RNA-sequencing was conducted to identify hypoxia-related genes. The potential functions of Fascin-1 were evaluated by western blot, transwell migration and invasion assays, sphere-formation assay, tumor xenograft growth, gelatin zymography analysis, immunofluorescence, cell viability assay, soft agar assay, and flow cytometry. We found that Fascin-1 was upregulated by hypoxia in liver cancer cell lines, elevated in liver cancer patients and correlated with larger tumor size, lymph node metastasis, distant metastasis, and shorter overall survival. Knockdown of Fascin-1 suppressed migration, invasion, EMT, stemness, and tumor xenograft growth of liver cancer cells under both normoxia and hypoxia conditions, while forced Fascin-1 expression showed opposite effects. Moreover, hypoxia-induced upregulation of Fascin-1 was regulated by the Akt/Rac1 signaling, and inhibition of Akt/Rac1 signaling by EHop-016 and MK-2206 restrained migration, invasion, EMT, and stemness of liver cancer cells under hypoxia. Furthermore, Fascin-1 knockdown suppressed MMP-2 and MMP-9 expression, impaired actin cytoskeleton rearrangement, inactivated Hippo/YAP signaling, and increased Sorafenib sensitivity in liver cancer cells. Our study provided a novel insight of Fascin-1 in regulating migration, invasion, EMT, and stemness of liver cancer cells under normoxia and hypoxia conditions.

Download Full-text

Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression

Scientific Reports ◽

10.1038/s41598-017-09244-8 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 37

Author(s):

Jie Qin ◽

Yan Liu ◽

Yongkui Lu ◽

Meiling Liu ◽

Manli Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Hypoxia Inducible Factor ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Sirt1 Expression ◽

Hypoxia Inducible Factor 1

Download Full-text

Loss of LSR affects epithelial barrier integrity and tumor xenograft growth of CaCo-2 cells

Oncotarget ◽

10.18632/oncotarget.10425 ◽

2016 ◽

Vol 8 (23) ◽

pp. 37009-37022 ◽

Cited By ~ 13

Author(s):

Bernd A. Czulkies ◽

Justin Mastroianni ◽

Lisa Lutz ◽

Sarah Lang ◽

Carsten Schwan ◽

...

Keyword(s):

Tumor Xenograft ◽

Epithelial Barrier ◽

Barrier Integrity ◽

Xenograft Growth ◽

Tumor Xenograft Growth

Download Full-text

Circular RNA CDR1as Exerts Oncogenic Properties Partially through Regulating MicroRNA 641 in Cholangiocarcinoma

Molecular and Cellular Biology ◽

10.1128/mcb.00042-20 ◽

2020 ◽

Vol 40 (15) ◽

Cited By ~ 1

Author(s):

Dingyang Li ◽

Zhe Tang ◽

Zhiqiang Gao ◽

Pengcheng Shen ◽

Zhaochen Liu ◽

...

Keyword(s):

Cell Proliferation ◽

Target Genes ◽

Circular Rna ◽

Tumor Xenograft ◽

Mrna Levels ◽

Cell Behaviors ◽

Xenograft Growth ◽

Tumor Xenograft Growth

ABSTRACT It has been found that the circular RNA (circRNA) CDR1as is upregulated in cholangiocarcinoma (CCA) tissues. In this study, we tried to explore the roles of CDR1as in CCA. CDR1as was overexpressed or knocked down in human CCA cells to assess the effects of CDR1as on cell behaviors and tumor xenograft growth. In vitro, the CDR1as level was significantly increased in CCA cell lines. The results showed that CDR1as promoted the cell proliferation, migration, invasion, and activation of the AKT3/mTOR pathway in CCA cells. Moreover, miR-641, a predicted target microRNA (miRNA) of CDR1as, could partially reverse the effects of CDR1as on cell behaviors in CCA cells. Furthermore, CDR1as improved tumor xenograft growth, and it could be attenuated by miR-641 in vivo. Additionally, CDR1as expression was inversely correlated with miR-641 in CCA cells, and miR-641 could directly bind with CDR1as and its target genes, the AKT3 and mTOR genes. Mechanistically, CDR1as could bind with miR-641 and accelerate miR-641 degradation, which possibly leads to the upregulation of the relative mRNA levels of AKT3 and mTOR in RBE cells. In conclusion, our findings indicated that CDR1as might exert oncogenic properties, at least partially, by regulating miR-641 in CCA. CDR1as and miR-641 could be considered therapeutic targets for CCA.

Download Full-text