title: Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer.
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.
authors: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors: Shigeru
authors: S
authors: Hashimoto
authors: Division of Diagnostic Pathology, Keio University Hospital, Tokyo 160-0016, Japan.
authors: Shuji
authors: S
authors: Mikami
authors: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors: Hirokazu
authors: H
authors: Sugino
authors: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors: Ayumu
authors: A
authors: Yoshikawa
authors: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors: Ari
authors: A
authors: Hashimoto
authors: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors: Yasuhito
authors: Y
authors: Onodera
authors: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.|Department of Gastroenterological Surgery II, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors: Shotaro
authors: S
authors: Furukawa
authors: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors: Haruka
authors: H
authors: Handa
authors: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors: Tsukasa
authors: T
authors: Oikawa
authors: Department of Pathology, Keio University School of Medicine, Tokyo 160-0016, Japan.
authors: Yasunori
authors: Y
authors: Okada
authors: Department of Urology, Keio University School of Medicine, Tokyo 160-0016, Japan.
authors: Mototsugu
authors: M
authors: Oya
authors: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors: Hisataka
authors: H
authors: Sabe
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D000077210:Sunitinib; D014230:Triazoles / Q000494:pharmacology
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D000089982:ADP-Ribosylation Factor 6; D000577:Amides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D007211:Indoles; D007555:Isoxazoles; D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; C109970:PSD protein, human; D011422:Propionates; D011725:Pyridines; D011758:Pyrroles; D049368:Receptors, Lysophosphatidic Acid; C516025:SecinH3; D014230:Triazoles; C108830:Y 27632; C401859:temsirolimus; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse; C032881:lysophosphatidic acid; D000077210:Sunitinib; D020123:Sirolimus