Lysophosphatidic acid (LPA)-induced vasodilator-stimulated phosphoprotein mediates lamellipodia formation to initiate motility in PC-3 prostate cancer cells

Yutaka Hasegawa, Mandi Murph, Shuangxing Yu, Gabor Tigyi, Gordon Mills

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Prostate cancer remains the most frequently diagnosed malignancy and the second leading cause of cancer mortality among men in the United States. Hormone refractory, metastatic disease has no molecular therapeutics to date and survival is poor. Lysophosphatidic acid (LPA) is a bioactive lipid exhibiting motility, invasive, growth, proliferative and survival effects in multiple cancer cell lineages. Cells express different combinations of LPA-specific G protein-coupled receptors, LPA1, LPA2 LPA3, and LPA4 as well as other LPA receptors, which bind LPA and thereby regulate lipid signaling. The role of specific LPA receptors in functional outcomes of lysolipid signaling remains to be fully elucidated in prostate cancer. We hypothesized that LPA can initiate cell migration through specific LPA receptors by activating actin-associating proteins involved in motility, including the vasodilator-stimulated phosphoprotein (VASP). In the present study, we demonstrate that LPA-induced lamellipodia formation in cells is dependent on LPA receptor-mediated phosphorylation of VASP, demonstrating a previously unknown regulation by LPA. LPA induces phosphorylation of VASP at Ser(157), through protein kinase A (PKA) since the stimulation was abrogated by PKA inhibition. In addition, we found that the effects of LPA-induced lamellipodia formation and migration were reduced by knockdown of either VASP or LPA receptor expression, suggesting that LPA receptor-induced VASP phosphorylation is a critical mediator of migration initiation. Thus the LPA2 and LPA3 receptors, in addition to the previously implicated LPA1 receptor, play a role in cellular motility potentially contributing to invasion and metastases. Emerging drugs targeting the LPA pathway may be beneficial for the treatment of metastatic progression in prostate cancer.

Original languageEnglish (US)
Pages (from-to)54-69
Number of pages16
JournalMolecular Oncology
Volume2
Issue number1
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

Fingerprint

Lysophosphatidic Acid Receptors
Pseudopodia
Prostatic Neoplasms
Phosphorylation
Cyclic AMP-Dependent Protein Kinases
Lipids
lysophosphatidic acid
vasodilator-stimulated phosphoprotein
Survival
Second Primary Neoplasms
Cell Lineage
Drug Delivery Systems
G-Protein-Coupled Receptors
Cell Movement
Actins
Neoplasms
Hormones
Neoplasm Metastasis

Keywords

  • Lamellipodia
  • Lysophosphatidic acid (LPA)
  • Protein kinase A (PKA)
  • Vasodilator-stimulated phosphoprotein (VASP)

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

Lysophosphatidic acid (LPA)-induced vasodilator-stimulated phosphoprotein mediates lamellipodia formation to initiate motility in PC-3 prostate cancer cells. / Hasegawa, Yutaka; Murph, Mandi; Yu, Shuangxing; Tigyi, Gabor; Mills, Gordon.

In: Molecular Oncology, Vol. 2, No. 1, 01.06.2008, p. 54-69.

Research output: Contribution to journalArticle

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