TY - JOUR
T1 - Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer
AU - Hashimoto, Shigeru
AU - Mikami, Shuji
AU - Sugino, Hirokazu
AU - Yoshikawa, Ayumu
AU - Hashimoto, Ari
AU - Onodera, Yasuhito
AU - Furukawa, Shotaro
AU - Handa, Haruka
AU - Oikawa, Tsukasa
AU - Okada, Yasunori
AU - Oya, Mototsugu
AU - Sabe, Hisataka
N1 - Funding Information:
We thank Y. Kado, H. Yoshino and E. Hayashi for their assistance, T. Kitamura for the Plat-E cells, T. Akagi for the pCX4-bsr vector, and H. A. Popiel for her critical reading of the manuscript. This work was supported by Grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan, and grants from the Takeda Science Foundation and the Mitsubishi Foundation to H.S.
PY - 2016/2/8
Y1 - 2016/2/8
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms10656
DO - 10.1038/ncomms10656
M3 - Article
C2 - 26854204
AN - SCOPUS:84957573832
SN - 2041-1723
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 10656
ER -
