title: Integrated omics-analysis reveals Wnt-mediated NAD+ metabolic reprogramming in cancer stem-like cells.
abstract: 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.
authors.affiliation: Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03760, Republic of Korea.|Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Jueun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kee
authors.affiliation: Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03760, Republic of Korea.|Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Soonki
authors.initials: S
authors.lastname: Min
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Ki Cheong
authors.initials: KC
authors.lastname: Park
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Sunho
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Hwang
authors.affiliation: Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Do Hyun
authors.initials: DH
authors.lastname: Ryu
authors.affiliation: Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03760, Republic of Korea.|Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Geum-Sook
authors.initials: GS
authors.lastname: Hwang
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.|Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.|BK21 PLUS Projects for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.|Open NBI Convergence Technology Research Laboratory, Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Cheong
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D003600:Cytosol / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D020287:In Situ Nick-End Labeling; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000378:metabolism; D055432:Metabolomics / Q000379:methods; D009243:NAD / Q000378:metabolism*; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology*; D018874:Spheroids, Cellular; D000073940:Transcription Factor 4 / Q000235:genetics; D014162:Transfection; D060449:Wnt Signaling Pathway
chemical_list: D008562:Membrane Glycoproteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D009243:NAD; D009249:NADP; C024376:NAADP; D000469:Alkaline Phosphatase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium
keywords: Wnt signaling; calcium signaling; cancer stem cells; integrated analysis; metabolic reprogramming