Mitogenic action of lysophosphatidic acid and phosphatidic acid on fibroblasts. Dependence on acyl-chain length and inhibition by suramin
| Autor: | R L van der Bend, A van Rijswijk, Wouter H. Moolenaar, W J van Blitterswijk, E J van Corven, Kees Jalink |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
DNA Replication
Suramin Phospholipid Phosphatidic Acids Biology Biochemistry Cell Line Structure-Activity Relationship chemistry.chemical_compound Lysophosphatidic acid medicine Animals Fibroblast Molecular Biology IC50 chemistry.chemical_classification Epidermal Growth Factor DNA synthesis Endothelins Fatty acid Cell Biology Phosphatidic acid Kinetics medicine.anatomical_structure chemistry lipids (amino acids peptides and proteins) Lysophospholipids biological phenomena cell phenomena and immunity Cell Division Thymidine Research Article medicine.drug |
| Zdroj: | Europe PubMed Central |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj2810163 |
| Popis: | Lysophosphatidic acid (LPA) is a naturally occurring phospholipid with growth-factor-like activities [van Corven, Groenink, Jalink, Eichholtz & Moolenaar (1989) Cell 45, 45-54]. We have examined various structural analogues of LPA for their ability to stimulate DNA synthesis in quiescent fibroblasts. When the acyl-chain length is varied, the rank order of mitogenic potency is: 1-oleoyl LPA congruent to 1-palmitoyl LPA greater than 1-myristoyl LPA greater than 1-lauroyl LPA greater than 1-decanoyl LPA; the last compound shows almost no activity over the concentration range tested (1-100 microM). An ether-linked LPA (1-O-hexadecylglycerol 3-phosphate) has much decreased mitogenic activity as compared with the ester-linked analogue at concentrations less than 25 microM, and becomes cytotoxic at higher concentrations. Hexadecylphosphate, which lacks a glycerol backbone, has negligible activity. On a molar basis, diacyl phosphatidic acid (PA) is about equally potent as the corresponding LPA analogue, showing similar acyl-chain-length dependence; the data argue against the possibility that the mitogenic action of PA is due to contaminating traces of LPA. Although the short-chain analogues of LPA and PA fail to antagonize the action of long-chain (L)PAs, the polyanionic drug suramin inhibits LPA- and PA-induced, DNA synthesis in a reversible and dose-dependent manner, at concentrations [IC50 (concn. giving 50% inhibition) approximately 70 microM] that do not affect epidermal-growth-factor-induced DNA synthesis. Suramin appears to act in the early G0/G1 phase of the cell cycle, blocking immediate responses to LPA such as phosphoinositide hydrolysis. We conclude that both LPA and PA can function as growth-promoting phospholipids, with the fatty acid chain length being a major determinant of mitogenic potency. |
| Databáze: | OpenAIRE |
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