Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting
| Autor: | Zhou Jy, Bo Li, Chen Yan, Sai-Juan Chen, Zhao Wl, Jun Hu, Juan Bian, Wu Ll, Yibin Wang, Liwei Wang, Jie Xiong, Yuanjin Zhao |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Choline kinase Apoptosis Biology Lymphoma T-Cell Choline chemistry.chemical_compound Mice Animals Choline Kinase Humans Molecular Targeted Therapy Enzyme Inhibitors Protein kinase B Aged Hematology Middle Aged Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Oncology chemistry Tumor progression Cancer cell Cancer research Phosphorylation Female Original Article Signal transduction |
| Zdroj: | Blood Cancer Journal |
| ISSN: | 2044-5385 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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