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Mol Biosyst. 2015 Dec;11(12):3378-86. doi: 10.1039/c5mb00525f.

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

Author information

1
Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02 Helios Building, 138667, Singapore and Department of Biological Sciences, Chonnam National University, Gwangju, Korea.
2
Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02 Helios Building, 138667, Singapore.
3
Global Drug Discovery, Therapeutic Research Group Oncology/Gynecological Therapies, Tumor Metabolism, Bayer Pharma AG, Berlin, Germany.
4
Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02 Helios Building, 138667, Singapore and Department of Chemistry & MedChem Program of Life Sciences Institute, National University of Singapore, 117543, Singapore. chmcyt@nus.edu.sg.

Abstract

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.

PMID:
26469267
DOI:
10.1039/c5mb00525f
[Indexed for MEDLINE]

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