Integrated omics-analysis reveals Wnt-mediated NAD+ metabolic reprogramming in cancer stem-like cells
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Jueun Lee1,2,*, Hyun Jung Kee3,*, Soonki Min1,2, Ki Cheong Park3, Sunho Park4, Tae Hyun Hwang4, Do Hyun Ryu2, Geum-Sook Hwang1,5, Jae-Ho Cheong3,6,7,8
1Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03760, Republic of Korea
2Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea
3Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
4Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
5Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea
6Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
7BK21 PLUS Projects for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
8Open NBI Convergence Technology Research Laboratory, Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
*These authors contributed equally to this work
Geum-Sook Hwang, email: [email protected]
Jae-Ho Cheong, email: [email protected]
Keywords: calcium signaling, cancer stem cells, integrated analysis, metabolic reprogramming, Wnt signaling
Received: November 29, 2015 Accepted: May 22, 2016 Published: July 6, 2016
Abnormal tumor cell metabolism is a consequence of alterations in signaling pathways that provide critical selective advantage to cancer cells. However, a systematic characterization of the metabolic and signaling pathways altered in cancer stem-like cells (CSCs) is currently lacking. Using nuclear magnetic resonance and mass spectrometry, we profiled the whole-cell metabolites of a pair of parental (P-231) and stem-like cancer cells (S-231), and then integrated with whole transcriptome profiles. We identified elevated NAAD+ in S-231 along with a coordinated increased expression of genes in Wnt/calcium signaling pathway, reflecting the correlation between metabolic reprogramming and altered signaling pathways. The expression of CD38 and ALP, upstream NAAD+ regulatory enzymes, was oppositely regulated between P- and S-231; high CD38 strongly correlated with NAADP in P-231 while high ALP with NAAD+ levels in S-231. Antagonizing Wnt activity by dnTCF4 transfection reversed the levels of NAAD+ and ALP expression in S-231. Of note, elevated NAAD+ caused a decrease of cytosolic Ca2+ levels preventing calcium-induced apoptosis in nutrient-deprived conditions. Reprograming of NAD+ metabolic pathway instigated by Wnt signaling prevented cytosolic Ca2+ overload thereby inhibiting calcium-induced apoptosis in S-231. These results suggest that “oncometabolites” resulting from cross talk between the deranged core cancer signaling pathway and metabolic network provide a selective advantage to CSCs.
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