Lysophosphatidic acid stimulates ovarian cancer cell migration via a Ras-MEK kinase 1 pathway

Dafang Bian, Shibing Su, Chitladda Mahanivong, Robert K. Cheng, Qiwei Han, Zhixing K. Pan, Peiqing Sun, Shuang Huang

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Abstract

Lysophosphatidic acid (LPA) is present at high concentrations in ascites and plasma of ovarian cancer patients. Studies conducted in experimental models demonstrate that LPA promotes ovarian cancer invasion/metastasis by up-regulating protease expression, elevating protease activity, and enhancing angiogenic factor expression. In this study, we investigated the effect of LPA on ovarian cancer migration, an essential component of cancer cell invasion. LPA stimulates both chemotaxis and chemokinesis of ovarian cancer cells and LPA-stimulated cell migration is GI dependent. Moreover, constitutively active H-Ras enhances ovarian cancer cell migration, whereas dominant negative H-Ras blocks LPA-stimulated cell migration, suggesting that Ras works downstream of Gi to mediate LPA-stimulated cell migration. Interestingly, H-Ras mutants that specifically activate Raf-1, Ral-GDS, or phosphatidylinositol 3′-kinase are unable to significantly enhance ovarian cancer cell migration, suggesting that a Ras downstream effector distinct from Raf-1, Ral-GDS, and phosphatidylinositol 3′-kinase is responsible for LPA-stimulated cell migration. In this article, we demonstrate that LPA activates mitogen-activated protein kinase kinase 1 (MEKK1) in a G i-Ras-dependent manner and that MEKK1 activity is essential for LPA-stimulated ovarian cancer cell migration. Inhibitors that block MEKK1 downstream pathways, including MEK1/2, MKK4/7, and nuclear factor-κB pathways, do not significantly alter LPA-stimulated cell migration. Instead, LPA induces the redistribution of focal adhesion kinase to focal contact regions of the cytoplasm membrane, and this event is abolished by pertussis toxin, dominant negative H-Ras, or dominant negative MEKK1. Our studies thus suggest that the Gi-Ras-MEKK1 signaling pathway mediates LPA-stimulated ovarian cancer cell migration by facilitating focal adhesion kinase redistribution to focal contacts.

Original languageEnglish (US)
Pages (from-to)4209-4217
Number of pages9
JournalCancer Research
Volume64
Issue number12
DOIs
StatePublished - Jun 15 2004

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MAP Kinase Kinase Kinase 1
Ovarian Neoplasms
Cell Movement
MAP Kinase Kinase 1
ral Guanine Nucleotide Exchange Factor
Phosphatidylinositol 3-Kinase
Focal Adhesion Protein-Tyrosine Kinases
Focal Adhesions
lysophosphatidic acid
Peptide Hydrolases
Angiogenesis Inducing Agents
Pertussis Toxin
Chemotaxis
Cellular Structures

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bian, D., Su, S., Mahanivong, C., Cheng, R. K., Han, Q., Pan, Z. K., ... Huang, S. (2004). Lysophosphatidic acid stimulates ovarian cancer cell migration via a Ras-MEK kinase 1 pathway. Cancer Research, 64(12), 4209-4217. https://doi.org/10.1158/0008-5472.CAN-04-0060

Lysophosphatidic acid stimulates ovarian cancer cell migration via a Ras-MEK kinase 1 pathway. / Bian, Dafang; Su, Shibing; Mahanivong, Chitladda; Cheng, Robert K.; Han, Qiwei; Pan, Zhixing K.; Sun, Peiqing; Huang, Shuang.

In: Cancer Research, Vol. 64, No. 12, 15.06.2004, p. 4209-4217.

Research output: Contribution to journalArticle

Bian, D, Su, S, Mahanivong, C, Cheng, RK, Han, Q, Pan, ZK, Sun, P & Huang, S 2004, 'Lysophosphatidic acid stimulates ovarian cancer cell migration via a Ras-MEK kinase 1 pathway', Cancer Research, vol. 64, no. 12, pp. 4209-4217. https://doi.org/10.1158/0008-5472.CAN-04-0060
Bian, Dafang ; Su, Shibing ; Mahanivong, Chitladda ; Cheng, Robert K. ; Han, Qiwei ; Pan, Zhixing K. ; Sun, Peiqing ; Huang, Shuang. / Lysophosphatidic acid stimulates ovarian cancer cell migration via a Ras-MEK kinase 1 pathway. In: Cancer Research. 2004 ; Vol. 64, No. 12. pp. 4209-4217.
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