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Mutant p53 regulates LPA signaling through lysophosphatidic acid phosphatase type 6.

ABSTRACT: Emerging evidence has indicated that high-grade serous ovarian cancer (HGSOC) originates in the fallopian tube, where the earliest known genetic lesion is the mutation of TP53. In addition to such genetic changes, HGSOC is characterized by altered metabolism, including the production of oncogenic lipids such as lysophosphatidic acid (LPA). To understand the crosstalk between TP53 mutations and LPA signaling, we utilized primary fallopian tube epithelial cells (FTEC) engineered to overexpress mutant p53. We found that gain-of-function (GOF) p53 mutations downregulated the LPA-degrading enzyme lysophosphatidic acid phosphatase type 6 (ACP6), leading to upregulation of focal adhesion signaling in an LPA-dependent manner. Although highly expressed in normal fallopian tube epithelium, ACP6 expression was significantly reduced in ovarian cancer tumors and early in situ lesions. Downregulation of ACP6 in ovarian cancer cells was necessary and sufficient to support HGSOC proliferation, adhesion, migration, and invasion. Using mouse models of metastasis, we established that attenuation of ACP6 expression was associated with increased tumor burden. Conversely, overexpression of ACP6 suppressed invasive behavior. These data identify an involvement of oncogenic p53 mutations in LPA signaling and HGSOC progression through regulation of ACP6 expression.

SUBMITTER: Chryplewicz A

PROVIDER: S-EPMC6435808 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Mutant p53 regulates LPA signaling through lysophosphatidic acid phosphatase type 6.

Chryplewicz Agnieszka A Tienda Samantha M SM Nahotko Dominik A DA Peters Pamela N PN Lengyel Ernst E Eckert Mark A MA

Scientific reports 20190326 1

Emerging evidence has indicated that high-grade serous ovarian cancer (HGSOC) originates in the fallopian tube, where the earliest known genetic lesion is the mutation of TP53. In addition to such genetic changes, HGSOC is characterized by altered metabolism, including the production of oncogenic lipids such as lysophosphatidic acid (LPA). To understand the crosstalk between TP53 mutations and LPA signaling, we utilized primary fallopian tube epithelial cells (FTEC) engineered to overexpress mut ...[more]

PMID: 30914657

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Project description:BackgroundIn the extracellular environment, lysophosphatidic acid (LPA) species are generated via autotaxin (ATX)-mediated hydrolysis of lysophospholipid precursors. Members of the LPA family are potent lipid mediators transmitting signals via six different G protein-coupled LPA receptors (LPAR1-6). The LPA signaling axis is indispensable for brain development and function of the nervous system; however, during damage of the central nervous system, LPA levels can increase and aberrant signaling events counteract brain function. Here, we investigated regulation of the ATX/LPA/LPAR axis in response to lipopolysaccharide-induced systemic inflammation in mice and potential neurotoxic polarization programs in LPA-activated primary murine microglia.MethodsIn vivo, LPAR1-6 expression was established by qPCR in whole murine brain homogenates and in FACS-sorted microglia. ELISAs were used to quantitate LPA concentrations in the brain and cyto-/chemokine secretion from primary microglia in vitro. Transcription factor phosphorylation was analyzed by immunoblotting, and plasma membrane markers were analyzed by flow cytometry. We used MAPK inhibitors to study signal integration by the JNK, p38, and ERK1/2 branches in response to LPA-mediated activation of primary microglia.ResultsUnder acute and chronic inflammatory conditions, we observed a significant increase in LPA concentrations and differential regulation of LPAR, ATX (encoded by ENPP2), and cytosolic phospholipase A2 (encoded by PLA2G4A) gene expression in the brain and FACS-sorted microglia. During pathway analyses in vitro, the use of specific MAPK antagonists (SP600125, SB203580, and PD98059) revealed that JNK and p38 inhibition most efficiently attenuated LPA-induced phosphorylation of proinflammatory transcription factors (STAT1 and -3, p65, and c-Jun) and secretion of IL-6 and TNFα. All three inhibitors decreased LPA-mediated secretion of IL-1β, CXCL10, CXCL2, and CCL5. The plasma membrane marker CD40 was solely inhibited by SP600125 while all three inhibitors affected expression of CD86 and CD206. All MAPK antagonists reduced intracellular COX-2 and Arg1 as well as ROS and NO formation, and neurotoxicity of microglia-conditioned media.ConclusionIn the present study, we show that systemic inflammation induces aberrant ATX/LPA/LPAR homeostasis in the murine brain. LPA-mediated polarization of primary microglia via MAPK-dependent pathways induces features reminiscent of a neurotoxic phenotype.

Project description:Background: Lysophosphatidic acid (LPA) is a small glycerophospholipid that acts as a potent extracellular signal in various biological processes and diseases. Our previous work demonstrated that the expression of the LPA receptors LPA1 and LPA3 is elevated in the early postnatal heart. However, the role of this stage-specific expression of LPA1 and LPA3 in the heart is unknown. Methods and Results: By using LPA3 and LPA1 knockout mice, and neonatal SD rats treated with Ki16425 (LPA1/LPA3 inhibitor), we found that the number of proliferating cardiomyocytes, detected by coimmunostaining pH3, Ki67 or BrdU with cardiac troponin T, was significantly decreased in the LPA3 knockout mice and the Ki16425-treated rats but not in the LPA1 knockout mice during the first week of postnatal life. Using a myocardial infarction (MI) model, we found that cardiac function and the number of proliferating cardiomyocytes were decreased in the neonatal LPA3 KO mice and increased in the AAV9-mediated cardiac-specific LPA3 overexpression mice. By using lineage tracing and AAV9-LPA3, we further found that LPA3 overexpression in adult mice enhances cardiac function and heart regeneration as assessed by pH3-, Ki67-, and Aurora B-positive cardiomyocytes and clonal cardiomyocytes after MI. Genome-wide transcriptional profiling and additional mechanistic studies showed that LPA induces cardiomyocyte proliferation through the PI3K/AKT, BMP-Smad1/5, Hippo/YAP and MAPK/ERK pathways in vitro, whereas only ERK was confirmed to be activated by LPA-LPA3 signaling in vivo. Conclusion: Our study reports that LPA3-mediated LPA signaling is a crucial factor for cardiomyocyte proliferation in the early postnatal heart. Cardiac-specific LPA3 overexpression improved cardiac function and promoted cardiac regeneration after myocardial injury induced by MI. This finding suggested that activation of LPA3 potentially through AAV-mediated gene therapy might be a therapeutic strategy to improve the outcome after MI.

Project description:The developmental process of central nervous system (CNS) myelin sheath formation is characterized by well-coordinated cellular activities ultimately ensuring rapid and synchronized neural communication. During this process, myelinating CNS cells, namely oligodendrocytes (OLGs), undergo distinct steps of differentiation, whereby the progression of earlier maturation stages of OLGs represents a critical step toward the timely establishment of myelinated axonal circuits. Given the complexity of functional integration, it is not surprising that OLG maturation is controlled by a yet fully to be defined set of both negative and positive modulators. In this context, we provide here first evidence for a role of lysophosphatidic acid (LPA) signaling via the G protein-coupled receptor LPA6 as a negative modulatory regulator of myelination-associated gene expression in OLGs. More specifically, the cell surface accessibility of LPA6 was found to be restricted to the earlier maturation stages of differentiating OLGs, and OLG maturation was found to occur precociously in Lpar6 knockout mice. To further substantiate these findings, a novel small molecule ligand with selectivity for preferentially LPA6 and LPA6 agonist characteristics was functionally characterized in vitro in primary cultures of rat OLGs and in vivo in the developing zebrafish. Utilizing this approach, a negative modulatory role of LPA6 signaling in OLG maturation could be corroborated. During development, such a functional role of LPA6 signaling likely serves to ensure timely coordination of circuit formation and myelination. Under pathological conditions as seen in the major human demyelinating disease multiple sclerosis (MS), however, persistent LPA6 expression and signaling in OLGs can be seen as an inhibitor of myelin repair. Thus, it is of interest that LPA6 protein levels appear elevated in MS brain samples, thereby suggesting that LPA6 signaling may represent a potential new druggable pathway suitable to promote myelin repair in MS.

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Mutant p53 regulates LPA signaling through lysophosphatidic acid phosphatase type 6.

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Mutant p53 regulates LPA signaling through lysophosphatidic acid phosphatase type 6.

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