Integrated omics-analysis reveals Wnt-mediated NAD+ metabolic reprogramming in cancer stem-like cells

Jueun Lee, Hyun Jung Kee, Soonki Min, Ki Cheong Park, Sunho Park, Tae Hyun Hwang, Do Hyun Ryu, Geum Sook Hwang, Jae Ho Cheong

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)48562-48576
Number of pages15
JournalOncotarget
Volume7
Issue number30
DOIs
StatePublished - Jan 1 2016

Keywords

  • Calcium signaling
  • Cancer stem cells
  • Integrated analysis
  • Metabolic reprogramming
  • Wnt signaling

ASJC Scopus subject areas

  • Oncology

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    Lee, J., Kee, H. J., Min, S., Park, K. C., Park, S., Hwang, T. H., Ryu, D. H., Hwang, G. S., & Cheong, J. H. (2016). Integrated omics-analysis reveals Wnt-mediated NAD+ metabolic reprogramming in cancer stem-like cells. Oncotarget, 7(30), 48562-48576. https://doi.org/10.18632/oncotarget.10432