Research Papers:
LC-MS-based metabolomics revealed SLC25A22 as an essential regulator of aspartate-derived amino acids and polyamines in KRAS-mutant colorectal cancer
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Abstract
Xiaona Li1, Arthur C.K. Chung1, Shangfu Li1, Lilan Wu1,2, Jiaying Xu3, Jun Yu3,4, Chichun Wong3,4 and Zongwei Cai1
1State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
2Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong, China
3Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
4Shenzhen Research Institute, The Chinese University of Hong Kong, Guangdong, China
Correspondence to:
Zongwei Cai, email: [email protected]
Chichun Wong, email: [email protected]
Keywords: KRAS-mutant colorectal cancer, SLC25A22, LC-MS, metabolomics
Received: July 27, 2017 Accepted: September 04, 2017 Published: September 20, 2017
ABSTRACT
SLC25A22, which encodes the mitochondrial glutamate transporter, is overexpressed in colorectal cancer (CRC) and is essential for the proliferation of CRC cells harboring KRAS mutations. However, the role of SLC25A22 on metabolic regulation in KRAS-mutant CRC cells has not been comprehensively characterized.
We performed non-targeted metabolomics, targeted metabolomics and isotope kinetic analysis of KRAS-mutant DLD1 cells with or without SLC25A22 knockdown using ultra-high-performance liquid chromatography (UHPLC) coupled to Orbitrap mass spectrometry (MS) or tandem MS (MS/MS).
Global metabolomics analysis identified 35 altered metabolites, which were attributed to alanine, aspartate and glutamate metabolism, urea cycle and polyamine metabolism. Targeted metabolomics including 24 metabolites revealed that most tricarboxylic acid (TCA) cycle intermediates, aspartate-derived asparagine, alanine and ornithine-derived polyamines were strongly down-regulated in SLC25A22 knockdown cells. Moreover, targeted kinetic isotope analysis showed that most of the 13C-labeled ornithine-derived polyamines were significantly decreased in SLC25A22 knockdown cells and culture medium. Exogenous addition of polyamines could significantly promote cell proliferation in DLD1 cells, highlighting their potential role as oncogenic metabolites that function downstream of SLC25A22-mediated glutamine metabolism.
Collectively, SLC25A22 acts as an essential metabolic regulator during CRC progression as it promotes the synthesis of aspartate-derived amino acids and polyamines in KRAS mutant CRC cells.
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