title: Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting.
abstract: Cancer cells have distinct metabolomic profile. Metabolic enzymes regulate key oncogenic signaling pathways and have an essential role on tumor progression. Here, serum metabolomic analysis was performed in 45 patients with T-cell lymphoma (TCL) and 50 healthy volunteers. The results showed that dysregulation of choline metabolism occurred in TCL and was related to tumor cell overexpression of choline kinase-α (Chokα). In T-lymphoma cells, pharmacological and molecular silencing of Chokα significantly decreased Ras-GTP activity, AKT and ERK phosphorylation and MYC oncoprotein expression, leading to restoration of choline metabolites and induction of tumor cell apoptosis/necropotosis. In a T-lymphoma xenograft murine model, Chokα inhibitor CK37 remarkably retarded tumor growth, suppressed Ras-AKT/ERK signaling, increased lysophosphatidylcholine levels and induced in situ cell apoptosis/necropotosis. Collectively, as a regulatory gene of aberrant choline metabolism, Chokα possessed oncogenic activity and could be a potential therapeutic target in TCL, as well as other hematological malignancies with interrupted Ras signaling pathways.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Xiong
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Bian
authors.affiliation: 1] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [2] Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [2] Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: L-L
authors.initials: LL
authors.lastname: Wu
authors.affiliation: Department of Nuclear Medicine, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Hu
authors.affiliation: Department of Nuclear Medicine, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: 1] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [2] Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Yan
authors.affiliation: 1] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [2] Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: W-L
authors.initials: WL
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002794:Choline / Q000097:blood*; D002797:Choline Kinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016399:Lymphoma, T-Cell / Q000097:blood* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; C517212:CHKA protein, human; D002797:Choline Kinase; D002794:Choline