LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells

Cancer Res. 2011 Dec 1;71(23):7301-11. doi: 10.1158/0008-5472.CAN-11-2381. Epub 2011 Oct 6.

Abstract

CD97, an adhesion-linked G-protein-coupled receptor (GPCR), is induced in multiple epithelial cancer lineages. We address here the signaling properties and the functional significance of CD97 expression in prostate cancer. Our findings show that CD97 signals through Gα12/13 to increase RHO-GTP levels. CD97 functioned to mediate invasion in prostate cancer cells, at least in part, by associating with lysophosphatidic acid receptor 1 (LPAR1), leading to enhanced LPA-dependent RHO and extracellular signal-regulated kinase activation. Consistent with its role in invasion, depletion of CD97 in PC3 cells resulted in decreased bone metastasis without affecting subcutaneous tumor growth. Furthermore, CD97 heterodimerized and functionally synergized with LPAR1, a GPCR implicated in cancer progression. We also found that CD97 and LPAR expression were significantly correlated in clinical prostate cancer specimens. Taken together, these findings support the investigation of CD97 as a potential therapeutic cancer target.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Cell Line, Tumor
  • Disease Progression
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • Guanosine Triphosphate / metabolism
  • Humans
  • Lysophospholipids / pharmacology*
  • Male
  • Neoplasm Invasiveness / genetics
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Lysophosphatidic Acid / genetics
  • Receptors, Lysophosphatidic Acid / metabolism*
  • Signal Transduction / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • ADGRE5 protein, human
  • Antigens, CD
  • Lysophospholipids
  • Receptors, G-Protein-Coupled
  • Receptors, Lysophosphatidic Acid
  • Guanosine Triphosphate
  • Extracellular Signal-Regulated MAP Kinases
  • GTP-Binding Protein alpha Subunits, G12-G13
  • rhoA GTP-Binding Protein
  • lysophosphatidic acid