Effect of oncogene activating mutations and kinase inhibitors on amino acid metabolism of human isogenic breast cancer cells

We investigated the changes in amino acid (AA) metabolism induced in MCF10A, a human mammary epithelial cell line, by the sequential knock-in of K-Ras and PI3K mutant oncogenes. Differentially regulated genes associated to AA pathways were identified on comparing gene expression patterns in the isog...

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Bibliographic Details
Published in:Molecular bioSystems 2015-01, Vol.11 (12), p.3378-3386
Main Authors: Kim, Eung-Sam, Samanta, Animesh, Cheng, Hui Shan, Ding, Zhaobing, Han, Weiping, Toschi, Luisella, Chang, Young Tae
Format: Article
Language:English
Subjects:
Amino Acids - metabolism
Antineoplastic Agents - pharmacology
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Cell Line, Tumor
Female
Gene Expression Regulation, Enzymologic - drug effects
Gene Expression Regulation, Neoplastic - drug effects
Humans
Intracellular Space - metabolism
Metabolic Networks and Pathways - drug effects
Mutation
Oncogenes - genetics
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins p21(ras) - genetics
Proto-Oncogene Proteins p21(ras) - metabolism
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Summary:We investigated the changes in amino acid (AA) metabolism induced in MCF10A, a human mammary epithelial cell line, by the sequential knock-in of K-Ras and PI3K mutant oncogenes. Differentially regulated genes associated to AA pathways were identified on comparing gene expression patterns in the isogenic cell lines. Additionally, we monitored the changes in the levels of AAs and transcripts in the cell lines treated with kinase inhibitors (REGO: a multi-kinase inhibitor, PI3K-i: a PI3K inhibitor, and MEK-i: a MEK inhibitor). In total, 19 AAs and 58 AA-associated transcripts were found to be differentially regulated by oncogene knock-in and by drug treatment. In particular, the multi-kinase and MEK inhibitor affected pathways in K-Ras mutant cells, whereas the PI3K inhibitor showed a major impact in the K-Ras/PI3K double mutant cells. These findings may indicate the dependency of AA metabolism on the oncogene mutation pattern in human cancer. Thus, future therapy might include combinations of kinase inhibitors and drug targeting enzymes of AA pathways.
ISSN:1742-206X
1742-2051
DOI:10.1039/c5mb00525f