Autotaxin and LPA1 and LPA5 Receptors Exert Disparate Functions in Tumor Cells versus the Host Tissue Microenvironment in Melanoma Invasion and Metastasis

Lee, Sue-Chin; Fujiwara, Yuko; Liu, Jianxiong; Yue, Junming; Shimizu, Yasuhiko; Norman, Dean C.; Wang, Yaohong; Tsukahara, Ryoko; Szabó, Erzsébet; Patil, Renukadevi; Banerjee, Souvik; Miller, Duane D.; Balázs, Louisa; Ghosh, Manik C.; Waters, Christopher M.; Oravecz, Tamás; Tigyi, Gábor

doi:10.1158/1541-7786.mcr-14-0263

Cited by 83 publications

(66 citation statements)

References 49 publications

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“…In a larger context the present findings concerning the radiation-induced upregulation of the ATX-LPA 2 signaling axis, it will be of great interest to investigate how radiation therapy affects ATX activity and LPA production, given that to both ATX and LPA were attributed with playing a major role in metastasis, chemo- and radiation-resistance of several cancers [15, 49-51]. …”

Section: Resultsmentioning

confidence: 99%

The autotaxin–LPA 2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair

Balogh

Shimizu

Lee

et al. 2015

Cellular Signalling

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In this study we characterized the effects of radiation injury on the expression and function of the autotaxin (ATX)-LPA2 GPCR axis. In IEC-6 crypt cells and jejunum enteroids quantitative RT-PCR showed a time- and dose-dependent upregulation of lpa2 in response to γ-irradiation that was abolished by mutation of the NF-κB site in the lpa2 promoter or by inhibition of ATM/ATR kinases with CGK-733, suggesting that lpa2 is a DNA damage response gene upregulated by ATM via NF-κB. The resolution kinetics of the DNA damage marker γ-H2AX in LPA-treated IEC-6 cells exposed to γ-irradiation was accelerated compared to vehicle, whereas pharmacological inhibition of LPA2 delayed the resolution of γ-H2AX. In LPA2-reconstituted MEF cells lacking LPA1&3 the levels of γ-H2AX decreased rapidly, whereas in Vector MEF were high and remained sustained. Inhibition of ERK1&2 or PI3K/AKT signaling axis by pertussis toxin or the C311A/C314A/L351A mutation in the C-terminus of LPA2 abrogated the effect of LPA on DNA repair. LPA2 transcripts in Lin−Sca-1+c-Kit+ enriched for bone marrow stem cells were 27- and 5-fold higher than in common myeloid or lymphoid progenitors, respectively. Furthermore, after irradiation higher residual γ-H2AX levels were detected in the bone marrow or jejunum of irradiated LPA2-KO mice compared to WT mice. We found that γ-irradiation increases plasma ATX activity and LPA level that is in part due to the previously established radiation-induced upregulation of TNFα. These findings identify ATX and LPA2 as radiation-regulated genes that appear to play a physiological role in DNA repair.

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Section: Resultsmentioning

confidence: 99%

The autotaxin–LPA 2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair

Balogh

Shimizu

Lee

et al. 2015

Cellular Signalling

Self Cite

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“…89 A recent research suggested that LPAR5 exerts an anti-invasive action in melanoma cells; host LPAR5 promotes melanoma-derived invasion and lung metastasis. 59 These findings implicated that tumor and stromal LPAR might play different roles in invasion and the seeding of metastasis. In a study about prostate cancer, authors showed that enhanced LPAR6 signaling promoted migration of androgen-independent prostate cancer cells, and knockdown of LPAR6 actually caused the opposite effect.…”

Section: Expression Of Atx/lpa Axis In Cancermentioning

confidence: 94%

The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

et al. 2017

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Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1-6). This review provides an overview of the autotaxin/lysophosphatidate axis and collates current knowledge regarding its specific role in pancreatic cancer. With a deeper understanding of the critical role of the autotaxin/lysophosphatidate axis in pancreatic cancer, targeting autotaxin or lysophosphatidate receptor may be a potential and promising strategy for cancer therapy.

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“…Conversely, decreasing plasma LPA concentrations FBS has been used as a source of ATX to test the effi cacy of novel ATX inhibitors in the FS-3 assay ( 45,46 ), but our work now shows this assay detects little true ATX activity unless lysophospholipids are removed from the serum. Similar problems are likely to occur if fl uorescent probes are used to measured ATX activity in concentrated conditioned medium from cell culture ( 32,47,48 ). This can result from the production of lysophospholipids by the cells or the addition of FBS to the medium.…”

Section: Inhibition Of Atx In Vivo Increases Adipose Tissue Atx Exprementioning

confidence: 98%

Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

Benesch

Zhao

Curtis

et al. 2015

Journal of Lipid Research

105

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This article is available online at http://www.jlr.org Autotaxin (ATX) is a secreted enzyme, which converts extracellular lysophosphatidylcholine (LPC) into lysophosphatidate (LPA). This is an important reaction in cell signaling because LPA activates at least six G proteincoupled receptors to increase cell division, survival, and migration ( 1, 2 ). ATX serves an essential function in embryonic development because ATX knockout mice die in utero at day 9.5 with defects in vasculogenesis and the development of the neural crest ( 3-6 ). In the postnatal organism, the major function of ATX appears to be in wound healing. ATX is produced in response to infl ammation to mediate wound repair. If the infl ammation is not resolved, then high ATX concentrations persist in association with infl ammatory diseases such as arthritis and infl ammatory bowel disease ( 1,7,8 ). In addition, infl ammatory bowel disease and hepatitis can progress to carcinogenesis in these organs ( 1 ). Signifi cantly, increased ATX activity is associated with the growth of breast tumors ( 9, 10 ) and the ATX gene is among the top 40 most upregulated in metastatic cancer ( 11 ). Blocking LPA production by inhibiting ATX activity with ONO-8430506 decreases the fi rst phase of breast tumor growth and subsequent metastasis by about 60 % in mice ( 9, 12 ). Conversely, increasing the low lipid phosphate phosphatase (LPP)1 activity in cancer cells so as to increase LPA turnover in the tumor and attenuate LPA signaling decreased breast tumor growth and metastasis in mice by about 80% ( 13 ). These studies emphasize the importance of ATX in controlling cell signaling in several physiological and pathological conditions. Consequently, it is important to understand how ATX activity and signaling by LPA are regulated. The present work focuses on the role of ATX and how its expression is controlled.Abstract Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and infl ammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. Howeve...

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Autotaxin and LPA1 and LPA5 Receptors Exert Disparate Functions in Tumor Cells versus the Host Tissue Microenvironment in Melanoma Invasion and Metastasis

Cited by 83 publications

References 49 publications

The autotaxin–LPA 2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair

The autotaxin–LPA 2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair

The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

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