Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer

Nat Commun. 2016 Feb 8;7:10656. doi: 10.1038/ncomms10656.

Abstract

Acquisition of mesenchymal properties by cancer cells is critical for their malignant behaviour, but regulators of the mesenchymal molecular machinery and how it is activated remain elusive. Here we show that clear cell renal cell carcinomas (ccRCCs) frequently utilize the Arf6-based mesenchymal pathway to promote invasion and metastasis, similar to breast cancers. In breast cancer cells, ligand-activated receptor tyrosine kinases employ GEP100 to activate Arf6, which then recruits AMAP1; and AMAP1 then binds to the mesenchymal-specific protein EPB41L5, which promotes epithelial-mesenchymal transition and focal adhesion dynamics. In renal cancer cells, lysophosphatidic acid (LPA) activates Arf6 via its G-protein-coupled receptors, in which GTP-Gα12 binds to EFA6. The Arf6-based pathway may also contribute to drug resistance. Our results identify a specific mesenchymal molecular machinery of primary ccRCCs, which is triggered by a product of autotaxin and it is associated with poor outcome of patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / metabolism*
  • Adult
  • Aged
  • Aged, 80 and over
  • Amides / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / pharmacology
  • Epithelial-Mesenchymal Transition*
  • Female
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism*
  • Guanine Nucleotide Exchange Factors
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • Indoles / pharmacology
  • Isoxazoles / pharmacology
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Lysophospholipids / metabolism*
  • Male
  • Mice, Nude
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Nerve Tissue Proteins / metabolism*
  • Propionates / pharmacology
  • Pyridines / pharmacology
  • Pyrroles / pharmacology
  • Receptors, Lysophosphatidic Acid / metabolism*
  • Signal Transduction
  • Sirolimus / analogs & derivatives
  • Sirolimus / pharmacology
  • Sunitinib
  • Triazoles / pharmacology

Substances

  • 3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid
  • Amides
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Guanine Nucleotide Exchange Factors
  • Indoles
  • Isoxazoles
  • Lysophospholipids
  • Nerve Tissue Proteins
  • PSD protein, human
  • Propionates
  • Pyridines
  • Pyrroles
  • Receptors, Lysophosphatidic Acid
  • SecinH3
  • Triazoles
  • Y 27632
  • temsirolimus
  • GTP-Binding Protein alpha Subunits, G12-G13
  • ADP-Ribosylation Factors
  • ADP-ribosylation factor 6
  • lysophosphatidic acid
  • Sunitinib
  • Sirolimus