Lysophosphatidic acid is a bioactive mediator in ovarian cancer

Fang, Xianjun; Schummer, Michèl; Mao, Muling; Yu, Shuangxing; Tabassam, Fazal H.; Swaby, Ramona F.; Hasegawa, Yutaka; Tanyi, János L.; LaPushin, Ruthie; Eder, Astrid; Jaffe, Robert B.; Erickson, J; Mills, Gordon B.

doi:10.1016/s1388-1981(02)00179-8

Cited by 248 publications

(290 citation statements)

References 53 publications

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“…Previously, it has been reported that LPA is present at high concentrations in ascites of ovarian cancer patients [20,21]. Furthermore, it has been demonstrated that LPA has very important roles in the pathogenesis of ovarian cancer cells [3,22]. LPA acts as a growth factor in ovarian cancer cells, resulting in proliferation of the cells [20].…”

Section: Discussionmentioning

confidence: 99%

“…LPA has been reported to induce cellular proliferation in primary ovarian carcinoma cells, prostate cancer cell lines, amnionic cells, chondrocytes, and so on [3][4][5]. LPA also induces cellular migration and invasion in fibroblasts or some cancer cells, such as ovarian cancer cells [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…LPA also induces cellular migration and invasion in fibroblasts or some cancer cells, such as ovarian cancer cells [6,7]. In terms of cell surface receptors for LPA, certain type of G-protein coupled receptor (GPCR) such as LPA 1 , LPA 2 , and LPA 3 have been reported [8,9]. In addition to LPA, other lysophospholipids including lysophosphatidylserine (LPS) and lysophosphatidylglycerol (LPG) also reported to act as bioactive lipid ligands [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Lysophosphatidylethanolamine stimulates chemotactic migration and cellular invasion in SK‐OV3 human ovarian cancer cells: Involvement of pertussis toxin‐sensitive G‐protein coupled receptor

Park¹,

Lee²,

Lee³

et al. 2007

FEBS Letters

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We investigated whether lysophosphatidylethanolamine (LPE) modulates cellular signaling in different cell types. SK-OV3 ovarian cancer cells and OVCAR-3 ovarian cancer cells were responsive to LPE. LPE-stimulated intracellular calcium concentration ([Ca 2+ ] i ) increase was inhibited by U-73122, suggesting that LPE stimulates calcium signaling via phospholipase C activation. Moreover, pertussis toxin (PTX) almost completely inhibited [Ca 2+ ] i increase by LPE, indicating the involvement of PTX-sensitive G-proteins. Furthermore, we found that LPE stimulated chemotactic migration and cellular invasion in SK-OV3 ovarian cancer cells. We examined the role of lysophosphatidic acid receptors on LPE-stimulated cellular responses using HepG2 cells transfected with different LPA receptors, and found that LPE failed to stimulate nuclear factor kappa B-driven luciferase. We suggest that LPE stimulates a membrane bound receptor, different from well known LPA receptors, resulting in chemotactic migration and cellular invasion in SK-OV3 ovarian cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lysophosphatidylethanolamine stimulates chemotactic migration and cellular invasion in SK‐OV3 human ovarian cancer cells: Involvement of pertussis toxin‐sensitive G‐protein coupled receptor

Park¹,

Lee²,

Lee³

et al. 2007

FEBS Letters

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“…[1][2][3][4] At the organ system level, LPA is implicated in complex physiological responses that include immunological competence, brain…”

Section: Introductionmentioning

confidence: 99%

α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

Jiang

Fujiwara

et al. 2007

ChemMedChem

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Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G-protein-coupled receptors (GPCRs) have important potential applications in cell biology and therapy. LPA GPCRs regulate cancer cell proliferation, invasion, angiogenesis, and biochemical resistance to chemotherapy-and radiotherapy-induced apoptosis. LPA and its analogues are also feedback inhibitors of the enzyme lysophospholipase D (lysoPLD, also known as autotaxin), a central regulator of invasion and metastasis. For cancer therapy, the ideal therapeutic profile would be a metabolically stabilized pan-LPA receptor antagonist that also inhibits lysoPLD. Herein we describe the synthesis of a series of novel α-substituted methylene phosphonate analogues of LPA. Each of these analogues contains a hydrolysis-resistant phosphonate mimic of the labile monophosphate of natural LPA. The pharmacological properties of these phosphono-LPA analogues were characterized in terms of LPA receptor subtype-specific agonist and antagonist activity using Ca 2+ mobilization assays in RH7777 and CHO cells expressing the individual LPA GPCRs. In particular, the methylene phosphonate LPA analogue is a selective LPA 2 agonist, whereas the corresponding α-hydroxymethylene phosphonate is a selective LPA 3 agonist. Most importantly, the α-bromomethylene and α-chloromethylene phosphonates show pan-LPA receptor subtype antagonist activity. The α-bromomethylene phosphonates are the first reported antagonists for the LPA 4 GPCR. Each of the α-substituted methylene phosphonates inhibits lysoPLD, with the unsubstituted methylene phosphonate showing the most potent inhibition. Finally, unlike many LPA analogues, none of these compounds activate the intracellular LPA receptor PPARγ.

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“…5,6 These LPA-activated signaling pathways are implicated in a number of biological processes, such as cell migration, proliferation, and survival, that are associated with the pathogenesis of many cancers, including ovarian cancer. 7 Additionally, LPA-activated signaling pathways have been implicated in other human diseases, including chronic inflammation, 8 fibrotic diseases, 9,10 and thrombosis. 11 Patients with ovarian cancer often present with an accumulation of ascites fluid in the intraperitoneal cavity which contains LPA at concentrations up to 80 μM.…”

mentioning

confidence: 99%

Dendrimer Conjugate of [4-(Tetradecanoylamino)benzyl]phosphonic Acid (S32826) as an Autotaxin Inhibitor

Fisher

Hilton-Bolt

Edwards

et al. 2013

ACS Med. Chem. Lett.

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Autotaxin is an extracellular phospholipase D that catalyzes the hydrolysis of lysophosphatidyl choline (LPC) to bioactive lipid lysophosphatidic acid (LPA). LPA has been implicated in many pathological processes relevant to cancer, including cell migration and invasion, proliferation, and survival. The most potent autotaxin inhibitor described to date is the LPA analogue S32826 (IC 50 5.6 nM). S32826 and many other autotaxin inhibitors are notably lipophilic, creating a need to improve their physical properties. Polymers are becoming an increasingly useful tool in the delivery of drugs and have the potential to improve the properties of small molecules. Herein we report the synthesis of a S32826 dendrimer conjugate and its biological evaluation. The conjugate was found to inhibit autotaxin activity using two different substrates and to decrease the migration of an ovarian cancer cell line modified to overexpress autotaxin. Furthermore, the conjugate potentiated activation of caspase 3/7 induced by carboplatin.

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Lysophosphatidic acid is a bioactive mediator in ovarian cancer

Cited by 248 publications

References 53 publications

Lysophosphatidylethanolamine stimulates chemotactic migration and cellular invasion in SK‐OV3 human ovarian cancer cells: Involvement of pertussis toxin‐sensitive G‐protein coupled receptor

Lysophosphatidylethanolamine stimulates chemotactic migration and cellular invasion in SK‐OV3 human ovarian cancer cells: Involvement of pertussis toxin‐sensitive G‐protein coupled receptor

α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

Dendrimer Conjugate of [4-(Tetradecanoylamino)benzyl]phosphonic Acid (S32826) as an Autotaxin Inhibitor

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