title: Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling.
abstract: Human cancer cell lines are used as important model systems to study molecular mechanisms associated with tumor growth, hereunder how genomic and biological heterogeneity found in primary tumors affect cellular phenotypes. We reconstructed Genome scale metabolic models (GEMs) for eleven cell lines based on RNA-Seq data and validated the functionality of these models with data from metabolite profiling. We used cell line-specific GEMs to analyze the differences in the metabolism of cancer cell lines, and to explore the heterogeneous expression of the metabolic subsystems. Furthermore, we predicted 85 antimetabolites that can inhibit growth of, or even kill, any of the cell lines, while at the same time not being toxic for 83 different healthy human cell types. 60 of these antimetabolites were found to inhibit growth in all cell lines. Finally, we experimentally validated one of the predicted antimetabolites using two cell lines with different phenotypic origins, and found that it is effective in inhibiting the growth of these cell lines. Using immunohistochemistry, we also showed high or moderate expression levels of proteins targeted by the validated antimetabolite. Identified anti-growth factors for inhibition of cell growth may provide leads for the development of efficient cancer treatment strategies.
authors: Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96, Gothenburg, Sweden.
authors: Pouyan
authors: P
authors: Ghaffari
authors: Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96, Gothenburg, Sweden.
authors: Adil
authors: A
authors: Mardinoglu
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden.
authors: Anna
authors: A
authors: Asplund
authors: Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96, Gothenburg, Sweden.
authors: Saeed
authors: S
authors: Shoaie
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden.
authors: Caroline
authors: C
authors: Kampf
authors: 1] Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21, Stockholm, Sweden [2] Department of Proteomics, KTH - Royal Institute of Technology, SE-106 91, Stockholm, Sweden.
authors: Mathias
authors: M
authors: Uhlen
authors: 1] Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96, Gothenburg, Sweden [2] Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21, Stockholm, Sweden.
authors: Jens
authors: J
authors: Nielsen
mesh_terms: D000963:Antimetabolites / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015894:Genome, Human; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008954:Models, Biological; D010480:Perhexiline / Q000494:pharmacology; D012313:RNA / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D012313:RNA; C577474:CPT1A protein, human; C542591:CPT1B protein, human; D002334:Carnitine O-Palmitoyltransferase; D010480:Perhexiline
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