Lysophosphatidic acid (LPA) stimulates invasion and metastatic colonization of ovarian cancer cells through Rac activation / 中华肿瘤杂志

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the mechanisms of lysophosphatidic acid (LPA) in stimulating invasion and metastatic colonization of ovarian cancer cells.</p><p><b>METHODS</b>The metastatic ability in vivo of ovarian cancer SK-OV3, HEY, OVCAR3, and IGROV1 cells was determined in tumor-bearing nude mouse models. Matrigel assay was used to detect the changes of response in vitro of ovarian cancer cells to LPA after Rac(-) or Rac(+) adenovirus treatment. LPA-induced Rho GTPase activation was detected by GST-fusion protein binding assay.</p><p><b>RESULTS</b>The peritoneal metastatic colonization assay showed overt metastatic colonization in mice receiving SK-OV3 and HEY cell inoculation, indicating that they are invasive cells. Metastatic colonization was not detected in animals receiving OVCAR3 and IGROV1 cells, indicating that these cells are non-invasive cells. In the matrigel invasion assay, exposure to LPA led to a notably greater migratory response in metastatic SK-OV3 and HEY cells (Optical density SK-OV3 cells 0.594±0.023 vs. 1.697±0.049, P<0.01; HEY cells 0.804±0.070 vs. 1.851±0.095, P<0.01). But LPA did little in the non-metastatic OVCAR3 and IGROV1 cells (Optical density A OVCAR3 cells 0.336±0.017 vs. 0.374±0.007, P>0.05; IGROV1 cells 0.491±0.036 vs. 0.479±0.061, P>0.05). LPA migratory responses of ovarian cancer cells were closely related to their metastatic colonization capabilities (r = 0.983, P<0.05). Rac(-) blocked the LPA response of invasive SK-OV3 and HEY cells (LPA-induced fold increase of cell migration SK-OV3 cells 2.988±0.095 vs. 0.997±0.100,P=0.01; HEY cells 2.404±0.059 vs. 0.901±0.072, P=0.01). But Rac(+) confered the non-invasive cells with LPA response and invasion capability (LPA-induced fold increase of cell migration OVCAR3 cells 1.072±0.080 vs. 1.898±0.078, P<0.01; IGROV1 cells 1.002±0.044 vs. 2.141±0.057, P<0.05). Among Rho GTPases, only Rac activation was different between ovarian cancer cell lines with different metastatic capability after LPA stimulation Cdc42 could not be activated in both the invasive and non-invasive cell lines. RhoA could be activated in both the invasive and non-invasive cell lines. Rac could be activated by LPA in the invasive ovarian cancer cell lines. However, Rac could not be activated in the non-invasive cell lines.</p><p><b>CONCLUSION</b>Lysophosphatidic acid stimulates invasion and metastasis of ovarian cancer cells through Rac activation.</p>