Constitutive and lysophosphatidic acid (LPA)-induced LPA production

Role of phospholipase D and phospholipase A2

Astrid M. Eder, Takayo Sasagawa, Muling Mao, Junken Aoki, Gordon Mills

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

Ascitic fluid and plasma from ovarian cancer patients, but not from patients with nongynecological tumors, contain elevated levels of the bioactive phospholipid lysophosphatidic acid (LPA). We show that ovarian cancer cells constitutively produce increased amounts of LPA as compared with normal ovarian epithelium, the precursor of ovarian epithelial cancer, or breast cancer cells. In addition, LPA, but not other growth factors, increases LPA production by the OVCAR-3 ovarian cancer cell line but not by normal ovarian epithelium or breast cancer cell lines. We show that phospholipase D activity contributes to both constitutive and LPA-induced LPA production by ovarian cancer cells. Constitutive and LPA-induced LPA synthesis by ovarian cancer cells is differentially regulated with respect to the requirement of specific phospholipase A2 (PLA2) subgroups. Group IB (pancreatic) secretory PLA2 plays a critical role in both constitutive and LPA-induced LPA formation, whereas group IIA (synovial) secretory PLA2 contributes to LPA-induced LPA production only. Calcium-dependent and/or - independent cytosolic PLA2s are required for constitutive LPA synthesis but do not play a role in LPA-induced LPA formation. LPA increases the proliferation of ovarian cancer cells, decreases sensitivity to cisplatin, the most commonly used drug in ovarian cancer, decreases apoptosis and anoikis, increases protease production, and increases production of neovascularization mediators. Thus, an understanding of the source and regulation of LPA production in ovarian cancer patients could identify novel targets for therapy.

Original languageEnglish (US)
Pages (from-to)2482-2491
Number of pages10
JournalClinical Cancer Research
Volume6
Issue number6
StatePublished - Jun 1 2000
Externally publishedYes

Fingerprint

Phospholipase D
Phospholipases A2
Ovarian Neoplasms
lysophosphatidic acid
Breast Neoplasms
Group IB Phospholipases A2
Epithelium
Group II Phospholipases A2
Anoikis
Cell Line
Ascitic Fluid

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Constitutive and lysophosphatidic acid (LPA)-induced LPA production : Role of phospholipase D and phospholipase A2. / Eder, Astrid M.; Sasagawa, Takayo; Mao, Muling; Aoki, Junken; Mills, Gordon.

In: Clinical Cancer Research, Vol. 6, No. 6, 01.06.2000, p. 2482-2491.

Research output: Contribution to journalArticle

Eder, Astrid M. ; Sasagawa, Takayo ; Mao, Muling ; Aoki, Junken ; Mills, Gordon. / Constitutive and lysophosphatidic acid (LPA)-induced LPA production : Role of phospholipase D and phospholipase A2. In: Clinical Cancer Research. 2000 ; Vol. 6, No. 6. pp. 2482-2491.
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abstract = "Ascitic fluid and plasma from ovarian cancer patients, but not from patients with nongynecological tumors, contain elevated levels of the bioactive phospholipid lysophosphatidic acid (LPA). We show that ovarian cancer cells constitutively produce increased amounts of LPA as compared with normal ovarian epithelium, the precursor of ovarian epithelial cancer, or breast cancer cells. In addition, LPA, but not other growth factors, increases LPA production by the OVCAR-3 ovarian cancer cell line but not by normal ovarian epithelium or breast cancer cell lines. We show that phospholipase D activity contributes to both constitutive and LPA-induced LPA production by ovarian cancer cells. Constitutive and LPA-induced LPA synthesis by ovarian cancer cells is differentially regulated with respect to the requirement of specific phospholipase A2 (PLA2) subgroups. Group IB (pancreatic) secretory PLA2 plays a critical role in both constitutive and LPA-induced LPA formation, whereas group IIA (synovial) secretory PLA2 contributes to LPA-induced LPA production only. Calcium-dependent and/or - independent cytosolic PLA2s are required for constitutive LPA synthesis but do not play a role in LPA-induced LPA formation. LPA increases the proliferation of ovarian cancer cells, decreases sensitivity to cisplatin, the most commonly used drug in ovarian cancer, decreases apoptosis and anoikis, increases protease production, and increases production of neovascularization mediators. Thus, an understanding of the source and regulation of LPA production in ovarian cancer patients could identify novel targets for therapy.",
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