Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma

Marchan, Rosemarie; Büttner, Bettina; Lambert, Jörg; Edlund, Karolina; Glaeser, Iris; Blaszkewicz, Meinolf; Leonhardt, Gregor; Marienhoff, Lisa; Kaszta, Darius; Anft, Moritz; Watzl, Carsten; Madjar, Katrin; Grinberg, Marianna; Rempel, Eugen; Hergenröder, Roland; Selinski, Silvia; Rahnenführer, Jörg; Lesjak, Michaela S.; Stewart, Joanna D.; Cadenas, Cristina; Hengstler, Jan G.

doi:10.1158/0008-5472.can-16-2065

Cited by 47 publications

(52 citation statements)

References 43 publications

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“…These findings indicated that high-dose DEX-inhibited tumor growth via the reduction of glucose metabolism enzymes expression, which starves the cancer cells of ATP and important amino acids/nucleic acid precursors. Gpam, Agpat2, and Dgat1 are critical enzymes involved in TG biosynthesis and Gpam overexpression correlates with cancer cell migration [44]. DEX injection decreases the hepatic TG accumulation in goats [45].…”

Section: Discussionmentioning

confidence: 99%

High-Dose Dexamethasone Manipulates the Tumor Microenvironment and Internal Metabolic Pathways in Anti-Tumor Progression

Hua

et al. 2020

IJMS

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High-dose dexamethasone (DEX) is used to treat chemotherapy-induced nausea and vomiting or to control immunotherapy-related autoimmune diseases in clinical practice. However, the underlying mechanisms of high-dose DEX in tumor progression remain unaddressed. Therefore, we explored the effects of high-dose DEX on tumor progression and the potential mechanisms of its anti-tumor function using immunohistochemistry, histological examination, real-time quantitative PCR (qPCR), and Western blotting. Tumor volume, blood vessel invasion, and levels of the cell proliferation markers Ki67 and c-Myc and the anti-apoptotic marker Bcl2 decreased in response to high-dose DEX. However, the cell apoptosis marker cleaved caspase 3 increased significantly in mice treated with 50 mg/kg DEX compared with controls. Some genes associated with immune responses were significantly downregulated following treatment with 50 mg/kg DEX e.g., Cxcl9, Cxcl10, Cd3e, Gzmb, Ifng, Foxp3, S100a9, Arg1, and Mrc1. In contrast, the M1-like tumor-associated macrophages (TAMs) activation marker Nos2 was shown to be increased. Moreover, the expression of peroxisome proliferator-activated receptors α and γ (Pparα and Pparg, respectively) was shown to be significantly upregulated in livers or tumors treated with DEX. However, high-dose DEX treatment decreased the expression of glucose and lipid metabolic pathway-related genes such as glycolysis-associated genes (Glut1, Hk2, Pgk1, Idh3a), triglyceride (TG) synthesis genes (Gpam, Agpat2, Dgat1), exogenous free fatty acid (FFA) uptake-related genes (Fabp1, Slc27a4, and CD36), and fatty acid oxidation (FAO) genes (Acadm, Acaa1, Cpt1a, Pnpla2). In addition, increased serum glucose and decreased serum TG and non-esterified fatty acid (NEFA) were observed in DEX treated-xenografted tumor mice. These findings indicate that high-dose DEX-inhibited tumor progression is a complicated process, not only activated by M1-like TAMs, but also decreased by the uptake and consumption of glucose and lipids that block the raw material and energy supply of cancer cells. Activated M1-like TAMs and inefficient glucose and lipid metabolism delayed tumor cell growth and promoted apoptosis. These findings have important implications for the application of DEX combined with drugs that target key metabolism pathways for tumor therapy in clinical practice.

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Section: Discussionmentioning

confidence: 99%

High-Dose Dexamethasone Manipulates the Tumor Microenvironment and Internal Metabolic Pathways in Anti-Tumor Progression

Hua

et al. 2020

IJMS

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“…Especially important conclusions provided by Marchan et al indicated that analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. The authors' results clearly showed how GPAM levels influence intracellular lysophosphatidic acid (LPA) levels to promote cell migration and tumor growth [31].…”

Section: Discussionmentioning

confidence: 99%

Coenzyme and cofactor metabolism belongs to biochemical processes significantly regulated in human granulosa cells collected after IVF during long-term primary in vitro culture

Nawrocki

Sibiak

Brązert

et al. 2019

Medical Journal of Cell Biology

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Granulosa cells (GCs) provide the microenvironment necessary for the development of the follicle and the maturation of the oocyte. GCs are associated with reproductive system function and the maintenance of pregnancy by participating in the synthesis of steroid hormones. Many authors point to new ways of using GCs in regenerative medicine and indicate the significant plasticity of this cell population, suggesting that GCs can undergo a transdifferentiation process. Employing primary in vitro cell cultures and high-throughput transcriptome analysis via Affymetrix microarrays, this study describes groups of genes associated with enzymatic reactions. 52 genes were identified belonging to four gene ontology biological process terms (GO BP): “coenzyme biosynthetic process”, “coenzyme metabolic process”, “cofactor biosynthetic process” and “cofactor metabolic process”. All identified genes showed reduction in the level of mRNA expression during long-term in vitro cultivation. Significanthe transcriptomic profile variability was exhibited for the genes (ELOVL5, ELOVL6 and GPAM) involved in enzymatic regulation of fatty acid metabolism.Running title: Enzymatic regulation in granulosa cells

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“…The situation remains challenging, since only the presence of T- and B-cells in tumor tissue does not seem to be sufficient to guarantee a favorable prognostic influence. Besides lymphocyte infiltration, further factors seem to be relevant, including the redox status, migration capacity, proliferation and the metabolic microenvironment (Hammad et al, 2016[ 6 ]; Cadenas et al, 2010[ 2 ], 2014[ 3 ]; Marchan et al, 2017[ 12 ]; Hassan et al, 2017[ 7 ]; Hellwig et al, 2016[ 9 ]; Stock et al, 2015[ 22 ]; Stewart et al, 2012[ 21 ]). A particularly critical aspect is to consider negative immune regulators, such as CTLA-4 and PD-1.…”

mentioning

confidence: 99%

Highlight report: Relevance of T-cells, B-cells and immune checkpoint factors for prognosis of breast cancer

Myllys

2019

EXCLI Journal; 18:Doc253; ISSN 1611-2156

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Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma

Cited by 47 publications

References 43 publications

High-Dose Dexamethasone Manipulates the Tumor Microenvironment and Internal Metabolic Pathways in Anti-Tumor Progression

High-Dose Dexamethasone Manipulates the Tumor Microenvironment and Internal Metabolic Pathways in Anti-Tumor Progression

Coenzyme and cofactor metabolism belongs to biochemical processes significantly regulated in human granulosa cells collected after IVF during long-term primary in vitro culture

Highlight report: Relevance of T-cells, B-cells and immune checkpoint factors for prognosis of breast cancer

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