The effects of group II phospholipase A2 on ras-induced metastasis.

Abstract

Expression of a ras oncogene and over-expression of the ras proto-oncogene occur in human neoplasias and are associated with transformation, tumorigenicity and metastasis in animal model systems (1–3). Therefore, the specific ras-induced alterations which facilitate primary tumor growth and metastasis are clearly of interest. The introduction of a ras gene product (p21) in eucaryotic cells causes transformation in vitro. This transformation has also been associated with increased phospholipase A2 (PLA2) activity and an increase of PLA2 reaction products (4–8). The immediate reaction products of PLA2 mediated hydrolysis of phospholipids are lysophospholipids and free fatty acids, for example arachidonic acid. These lipids can affect malignancy by different mechanisms. These lipids can also stimulate c-fas expression and cell proliferation (9,10). In addition, PLA2 activity is important in the regulation of the level of free arachidonic acid and thereby participates in the control of the synthesis of other lipid biomediators that can promote tumor growth and metastasis, such as prostaglandins and hydroxyeicosatetraenoic acids (11,12). Among the multiple PLA2s, only a subset is associated with release of arachidonic acid (reviewed in 13 and 14). Transfection of cells with the cDNA encoding for either the low molecular mass, group II PLA2 or the high molecular mass PLA2 (also termed cytosolic or cPLA2) results in increased release of arachidonic acid (15,16). The group II and the high molecular mass PLA2 activities are both increased in tumorigenic and metastatic ras-transfected rat embryo fibroblasts (CREF T24 cells) as compared to the parental cell line, the nontransformed, cloned rat embryo fibroblasts (CREF) [Guthridge et al., submitted]. Thus, we hypothesized that elevated PLA2 activity, resulting in elevated release of arachidonic acid, is important in ras-induced neoplasia. The present study explores this hypothesis. The effect of reducing group II PLA2 activity on the biological properties of ras-transfected cells is determined by analysis of CREF T24 cells transfected with vectors containing an antisense group II PLA2 cDNA. These antisense clones exhibit a reversion of transformed characteristics in vitro and a reduction of spontaneous metastases.KeywordsArachidonic AcidColony FormationSoft AgarPLA2 ActivitySpontaneous MetastasisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.