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

Shigeru Hashimoto; Shuji Mikami; Hirokazu Sugino; Ayumu Yoshikawa; Ari Hashimoto; Yasuhito Onodera; Shotaro Furukawa; Haruka Handa; Tsukasa Oikawa; Yasunori Okada; Mototsugu Oya; Hisataka Sabe

doi:10.1038/ncomms10656

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

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

Authors

Affiliations

¹ Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
² Division of Diagnostic Pathology, Keio University Hospital, Tokyo 160-0016, Japan.
³ Department of Gastroenterological Surgery II, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
⁴ Department of Pathology, Keio University School of Medicine, Tokyo 160-0016, Japan.
⁵ Department of Urology, Keio University School of Medicine, Tokyo 160-0016, Japan.

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 Factor 6
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
ADP-Ribosylation Factor 6
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
ARF6 protein, human
Arf6 protein, mouse
lysophosphatidic acid
Sunitinib
Sirolimus