Regulation of lysophosphatidate signaling by autotaxin and lipid phosphate phosphatases with respect to tumor progression, angiogenesis, metastasis and chemo-resistance

Samadi, Nasser; Bekele, Raie; Capatos, Dora; Venkatraman, Ganesh; Sarıahmetoğlu, Meltem; Brindley, David N.

doi:10.1016/j.biochi.2010.08.002

Cited by 104 publications

(125 citation statements)

References 139 publications

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“…Some of the genes that were most upregulated in decidual Mf as well as in M-CSF-and IL-10-polarized Mf were associated with cell metabolism and transport (Fig. 5D), including the folate receptor b (FOLR2) (45), selenoprotein SEPP1, the phospholipid transfer protein PLTP, and the tumor-promoting and angiogenic ENPP2 (46).…”

Section: Gene Expression Profile Of In Vitro Polarized Mf Compared Wimentioning

confidence: 99%

Macrophages at the Fetal–Maternal Interface Express Markers of Alternative Activation and Are Induced by M-CSF and IL-10

Svensson

Jenmalm

Matussek

et al. 2011

The Journal of Immunology

308

314

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During pregnancy, the maternal immune system is challenged by the presence of the fetus, which must be tolerated despite being semiallogeneic. Uterine mucosal (or decidual) macrophages (Mϕ), one of the major leukocyte populations at the fetal–maternal interface, have been implicated in fetal tolerance, but information regarding their regulation is scarce. In this study, we investigated the role of several factors potentially involved in the differentiation and polarization of decidual Mϕ with an in vitro Mϕ differentiation model. By using flow cytometry, we showed that M-CSF and IL-10 were potent inducers of M2 (immunoregulatory) Mϕ markers expressed on human decidual Mϕ (CD14, CD163, CD206, CD209). In contrast, proinflammatory stimuli, and unexpectedly also the Th2-associated IL-4 and IL-13, induced different patterns of expression, indicating that a Th2-dominated environment is not required for decidual Mϕ polarization. M-CSF/IL-10–stimulated and decidual Mϕ also showed similar cytokine secretion patterns, with production of IL-10 as well as IL-6, TNF, and CCL4. Conversely, the proinflammatory, LPS/IFN-γ–stimulated Mϕ produced significantly higher levels of TNF and no IL-10. We also used a gene array with 420 Mϕ-related genes, of which 100 were previously reported to be regulated in a global gene expression profiling of decidual Mϕ, confirming that M-CSF/IL-10–induced Mϕ are closely related to decidual Mϕ. Taken together, our results consistently point to a central role for M-CSF and in particular IL-10 in the shaping of decidual Mϕ with regulatory properties. These cytokines may therefore play an important role in supporting the homeostatic and tolerant immune milieu required for a successful pregnancy.

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Section: Gene Expression Profile Of In Vitro Polarized Mf Compared Wimentioning

confidence: 99%

Macrophages at the Fetal–Maternal Interface Express Markers of Alternative Activation and Are Induced by M-CSF and IL-10

Svensson

Jenmalm

Matussek

et al. 2011

The Journal of Immunology

308

314

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“…LPA decreases the expression of the tumor suppressor p53 [67] , thus increasing cancer cell survival and division. We discovered that LPA produces resistance to the cytotoxic effects of paclitaxel, a first line treatment for breast cancer [9,15,68] . This was confirmed [69] and extended since LPA produces resistance to the apoptotic effects of carboplatin [70] and radiation-induced cell death [14][15]71] .…”

Section: Overview Of the Atx-lpa-lpp Axis Atx -The Predominant Producmentioning

confidence: 99%

“…Further, the ATX gene is among the top 40 most upregulated genes in metastatic cancers [73] . ATX/LPA signaling is positively correlated with the invasive and metastatic potential of several cancers including melanoma, breast cancer, ovarian cancer, thyroid cancer, renal cell cancer, lung cancer, neuroblastoma, hepatocellular carcinoma and glioblastoma multiforme [15,74] .…”

Section: Overview Of the Atx-lpa-lpp Axis Atx -The Predominant Producmentioning

confidence: 99%

“…Overall, LPA signaling through at least six known G-protein-coupled receptors (LPA [1][2][3][4][5][6] ) stimulates cell survival and migration through the relative activations of (PI3K), ERK 1/2 , mTOR, Ca 2+ -transients, Rac, Rho and Ras, and these receptors are often overexpressed in cancer cells [15] . Like for ATX, mice that overexpress LPA 1 , LPA 2 or LPA 3 in mammary epithelium develop spontaneous metastatic mammary tumors [72] .…”

Section: Lpa Receptor Diversity and Signalingmentioning

confidence: 99%

“…Cancer cells also have increased expression of LPA receptors on their cell surface compared to normal and benign cells, and downregulated expression of LPPs [7,14] . Thus, a triad of increased LPA production by ATX, increased response to LPA by increased LPA receptor expression and decreased LPP activity to degrade LPA on the cell surface creates the per fect storm for cancer cell proliferation, migration, metas tasis and therapy resistance [7,10,[14][15] . Other inflammatory diseases including asthma, rheumatoid arthritis, lung and liver fibrosis, and inflammatory bowel diseases are also distinguished from normal physiology by increased ATX/LPA signaling.…”

Section: Introductionmentioning

confidence: 99%

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Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

2016

J Biomed Res

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Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased efficacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic inflammatory diseases.

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Autotaxin is a novel target of microRNA‐101‐3p

Lyu

Zhang

2019

FEBS Open Bio

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Autotaxin (ATX), a vital enzyme that generates lysophosphatidic acid (LPA), affects many biological processes, including tumorigenesis, via the ATX–LPA axis. In this study, we demonstrate that microRNA‐101‐3p (miR‐101‐3p), a well‐known tumor suppressor, downregulates ATX expression at the posttranscriptional level. We found that miR‐101‐3p inhibits ATX regulation by directly targeting a conserved sequence in the ATX mRNA 3′UTR. Moreover, we observed an inverse correlation between ATX and miR‐101‐3p levels in various types of cancer cells. ATX is highly expressed in several human cancers. Here, we verified that ATX expression is significantly inhibited by miR‐101‐3p in U87 and HCT116 cells. ATX downregulation contributed to the suppression of migration, invasion, and proliferation mediated by miR‐101‐3p; furthermore, the tumor‐suppressing activity of miR‐101‐3p was partially reduced by the addition of LPA in U87 cells. Our data suggest that ATX is a novel target of miR‐101‐3p.

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Regulation of lysophosphatidate signaling by autotaxin and lipid phosphate phosphatases with respect to tumor progression, angiogenesis, metastasis and chemo-resistance

Cited by 104 publications

References 139 publications

Macrophages at the Fetal–Maternal Interface Express Markers of Alternative Activation and Are Induced by M-CSF and IL-10

Macrophages at the Fetal–Maternal Interface Express Markers of Alternative Activation and Are Induced by M-CSF and IL-10

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

Autotaxin is a novel target of microRNA‐101‐3p

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