title: Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer.
abstract: Argininosuccinate synthetase 1 (ASS1) is a rate-limiting enzyme in arginine biosynthesis. Although ASS1 expression levels are often reduced in several tumors and low ASS1 expression can be a poor prognostic factor, the underlying mechanism has not been elucidated. In this study, we reveal a novel association between ASS1 and migration/invasion of endometrial tumors via regulation of mechanistic target of rapamycin complex (mTORC) 1 signaling. ASS1-knockout cells showed enhanced migration and invasion in response to arginine following arginine starvation. In ASS1-knockout cells, DEPTOR, an inhibitor of mTORC1 signal, was downregulated and mTORC1 signaling was more activated in response to arginine. ASS1 epigenetically enhanced DEPTOR expression by altering the histone methylation. Consistent with these findings, tumor cells at the invasive front of endometrioid carcinoma cases showed lower ASS1 and DEPTOR expression. Our findings suggest that ASS1 levels in each tumor cell are associated with invasion capability in response to arginine within the tumor microenvironment through mTORC1 signal regulation.
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohshima
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Tahara
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Kurashige
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Hori
authors.affiliation: Department of Bio-system Pharmacology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Hagiwara
authors.affiliation: Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Okuzaki
authors.affiliation: Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oki
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Wada
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Jun-Ichiro
authors.initials: JI
authors.lastname: Ikeda
authors.affiliation: Department of Bio-system Pharmacology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Morii
mesh_terms: D001120:Arginine / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D020159:Citrullinemia; D016889:Endometrial Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D001120:Arginine; C556139:DEPTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1