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 and Hisataka Sabe ()
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Shigeru Hashimoto: Graduate School of Medicine, Hokkaido University
Shuji Mikami: Keio University Hospital
Hirokazu Sugino: Graduate School of Medicine, Hokkaido University
Ayumu Yoshikawa: Graduate School of Medicine, Hokkaido University
Ari Hashimoto: Graduate School of Medicine, Hokkaido University
Yasuhito Onodera: Graduate School of Medicine, Hokkaido University
Shotaro Furukawa: Graduate School of Medicine, Hokkaido University
Haruka Handa: Graduate School of Medicine, Hokkaido University
Tsukasa Oikawa: Graduate School of Medicine, Hokkaido University
Yasunori Okada: Keio University School of Medicine
Mototsugu Oya: Keio University School of Medicine
Hisataka Sabe: Graduate School of Medicine, Hokkaido University

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10656

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