Electrospray Ionization Mass Spectrometry Analysis of Lysophospholipids in Human Ascitic Fluids: Comparison of the Lysophospholipid Contents in Malignant vs Nonmalignant Ascitic Fluids

Xiao, Yi; Schwartz, Benjamin; Washington, M. F.; Kennedy, Alexander W.; Webster, Kenneth; Belinson, Jerome L.; Xu, Yan

doi:10.1006/abio.2001.5000

Cited by 214 publications

(193 citation statements)

References 25 publications

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“…However, the mechanisms by which LPI is released and can signal inside the cells to stimulate proliferation were not known. It is noteworthy that levels of LPI and other lysophospholipids, such as lysophosphatidic acid, are increased in patients with ovarian cancer (Xiao et al, 2000(Xiao et al, , 2001Sutphen et al, 2004), corroborating our hypothesis that LPI may function as an autocrine factor that regulates cancer cell growth. Despite this evidence, signaling mediated by LPI and its potential role in cancer were poorly investigated, mostly because no specific receptor for LPI was known.…”

Section: Introductionsupporting

confidence: 86%

The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation

2010

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Recently, the orphan receptor G protein-coupled receptor 55 (GPR55) has been proposed as a potential cannabinoid receptor, although controversy remains on its physiological roles. Current evidence suggests a role for GPR55 as a receptor for the lysophospholipid lysophosphatidylinositol (LPI). In this study, we show that GPR55 is expressed in several prostate and ovarian cancer cell lines, both at the mRNA and at the protein level, and that it has a critical role in regulating proliferation and anchorage-independent growth. We further show that GPR55 mediates the effects of LPI in prostate and ovarian cancer cells. Indeed we demonstrate that LPI is able to induce calcium mobilization and activation of Akt and extracellular signal-regulated kinase (ERK)1/2 in these cells and that both pharmacological blockade of GPR55 and its downregulation using specific small interfering RNA strongly inhibits these processes. We further identify an autocrine loop by which LPI is synthesized by cytosolic phospholipase A2, pumped out of the cell by the ATP-binding cassette transporter ABCC1/MRP1, and is then able to initialize cascades downstream of GPR55. All together, these data demonstrate a role of LPI and its receptor GPR55 in cancer cells in activating an autocrine loop that regulates cell proliferation. These findings may have important implications for LPI as a novel cancer biomarker and for its receptor GPR55 as a potential therapeutic target.

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Section: Introductionsupporting

confidence: 86%

The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation

2010

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“…To compare HB-EGF with LPA for proliferation-promoting activity, SKOV3 cells were cultured either with HB-EGF or LPA in a culture medium containing peritoneal fluid of NO patients. Although the concentration of LPA in the peritoneal fluid of OVCA patients is reportedly from 10 to 20 mM (Xu et al, 1995;Westermann et al, 1998;Xiao et al, 2001), LPA (0 -50 mM) did not show any growth-promoting effect in the present cell system ( Figure 3A). In contrast, HB-EGF enhanced SKOV3 cell proliferation in a dosedependent manner ( Figure 3B), even at concentrations of 1 -10 ng ml À1 , which are comparable to the levels of HB-EGF in peritoneal fluid of OVCA patients.…”

Section: Resultsmentioning

confidence: 53%

“…Lysophophatidic acid and other ligands for G protein coupled receptors (GPCR) also transactivate EGFR through ectodomain shedding of HB-EGF or AR (Prenzel et al, 1999;Umata et al, 2001;Gschwind et al, 2003). In OVCA, LPA has been (Xu et al, 1995;Westermann et al, 1998;Xiao et al, 2001). In our study, LPA did not stimulate SKOV3 cell proliferation in the presence of peritoneal fluid of NO patients; however, the effect of LPA might be dependent on the cell system.…”

Section: Discussionmentioning

confidence: 99%

“…However, the growth-promoting properties of malignant effusions in vivo and in vitro have been shown to be independent of these peptide growth factors (Westermann et al, 1997). Recent biochemical analysis has revealed that one possible OCAF candidate is lysophophatidic acid (LPA) (Xu et al, 1995;Westermann et al, 1998;Xiao et al, 2001). Lysophophatidic acid is a simple phospholipid with numerous cellular effects including growth promotion, cell cycle progression and cytoskeletal organisation (Mills and Moolenaar, 2003).…”

mentioning

confidence: 99%

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Clinical significance of heparin-binding epidermal growth factor-like growth factor in peritoneal fluid of ovarian cancer

et al. 2005

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Epidermal growth factor receptor (EGFR) has been implicated in tumour growth and extension of ovarian cancer. Peritoneal fluid in ovarian cancer patients contains various growth factors that can promote tumour growth and extension. In order to investigate the clinical significance of EGFR ligands as activating factors of ovarian cancer, we examined the cell proliferation-promoting activity and the level of EGFR ligands in peritoneal fluid obtained from 99 patients. Proliferation-promoting activity in peritoneal fluid from 63 ovarian cancer patients (OVCA) was much higher than peritoneal fluid from 18 ovarian cyst patients (OVC) and 18 normal ovary patients (NO), and the activity was suppressed only by antibodies against EGFR or heparin-binding epidermal growth factor (HB-EGF). A large difference was observed in the level of EGFR ligands between HB-EGF and TGF-a or amphiregulin. The concentration of HB-EGF in OVCA significantly increased compared to that in OVC or NO (Po0.01). No significant difference in the concentration of TGF-a and amphiregulin was found between the OVCA and NO or OVC groups. In peritoneal fluid, HB-EGF is sufficiently elevated to activate cancer cells even at an early stage of OVCA. These results suggested that HB-EGF in peritoneal fluid might play a key role in cell survival and in the proliferation of OVCA.

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“…Therefore, the true LPA content may be higher than that estimated in the present study. Thus, the bioassay appears to be unsuitable for a quantitative measurement of LPA but may be superior to other methods, such as the combination of chromatography and mass spectrometry (42,43), for the evaluation of the active LPA that stimulates LPA receptors.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid (LPA) in Malignant Ascites Stimulates Motility of Human Pancreatic Cancer Cells through LPA1

Yamada

Sato

Komachi

et al. 2004

Journal of Biological Chemistry

160

153

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Cytokines and growth factors in malignant ascites are thought to modulate a variety of cellular activities of cancer cells and normal host cells. The motility of cancer cells is an especially important activity for invasion and metastasis. Here, we examined the components in ascites, which are responsible for cell motility, from patients and cancer cell-injected mice. Ascites remarkably stimulated the migration of pancreatic cancer cells. This response was inhibited or abolished by pertussis toxin, monoglyceride lipase, an enzyme hydrolyzing lysophosphatidic acid (LPA), and Ki16425 and VPC12249, antagonists for LPA receptors (LPA 1 and LPA 3 ), but not by an LPA 3 -selective antagonist. These agents also inhibited the response to LPA but not to the epidermal growth factor. In malignant ascites, LPA is present at a high level, which can explain the migration activity, and the fractionation study of ascites by lipid extraction and subsequent thin-layer chromatography indicated LPA as an active component. A significant level of LPA 1 receptor mRNA is expressed in pancreatic cancer cells with high migration activity to ascites but not in cells with low migration activity. Small interfering RNA against LPA 1 receptors specifically inhibited the receptor mRNA expression and abolished the migration response to ascites. These results suggest that LPA is a critical component of ascites for the motility of pancreatic cancer cells and LPA 1 receptors may mediate this activity. LPA receptor antagonists including Ki16425 are potential therapeutic drugs against the migration and invasion of cancer cells.

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Electrospray Ionization Mass Spectrometry Analysis of Lysophospholipids in Human Ascitic Fluids: Comparison of the Lysophospholipid Contents in Malignant vs Nonmalignant Ascitic Fluids

Cited by 214 publications

References 25 publications

The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation

The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation

Clinical significance of heparin-binding epidermal growth factor-like growth factor in peritoneal fluid of ovarian cancer

Lysophosphatidic Acid (LPA) in Malignant Ascites Stimulates Motility of Human Pancreatic Cancer Cells through LPA1

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