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

5 Citations (Scopus)

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 - 2016

Fingerprint

Neoplastic Stem Cells
Metabolic Networks and Pathways
NAD
Apoptosis
Calcium
Neoplasms
Wnt Signaling Pathway
Critical Pathways
Calcium Signaling
Transcriptome
Transfection
Mass Spectrometry
Magnetic Resonance Spectroscopy
Gene Expression
Food
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Integrated omics-analysis reveals Wnt-mediated NAD+ metabolic reprogramming in cancer stem-like cells. / Lee, Jueun; Kee, Hyun Jung; Min, Soonki; Park, Ki Cheong; Park, Sunho; Hwang, Tae Hyun; Ryu, Do Hyun; Hwang, Geum Sook; Cheong, Jae Ho.

In: Oncotarget, Vol. 7, No. 30, 2016, p. 48562-48576.

Research output: Contribution to journalArticle

Lee, J, Kee, HJ, Min, S, Park, KC, Park, S, Hwang, TH, Ryu, DH, Hwang, GS & Cheong, JH 2016, 'Integrated omics-analysis reveals Wnt-mediated NAD+ metabolic reprogramming in cancer stem-like cells', Oncotarget, vol. 7, no. 30, pp. 48562-48576. https://doi.org/10.18632/oncotarget.10432
Lee, Jueun ; Kee, Hyun Jung ; Min, Soonki ; Park, Ki Cheong ; Park, Sunho ; Hwang, Tae Hyun ; Ryu, Do Hyun ; Hwang, Geum Sook ; Cheong, Jae Ho. / Integrated omics-analysis reveals Wnt-mediated NAD+ metabolic reprogramming in cancer stem-like cells. In: Oncotarget. 2016 ; Vol. 7, No. 30. pp. 48562-48576.
@article{8f306a2026284420b5ecca52227b297c,
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.",
keywords = "Calcium signaling, Cancer stem cells, Integrated analysis, Metabolic reprogramming, Wnt signaling",
author = "Jueun Lee and Kee, {Hyun Jung} and Soonki Min and Park, {Ki Cheong} and Sunho Park and Hwang, {Tae Hyun} and Ryu, {Do Hyun} and Hwang, {Geum Sook} and Cheong, {Jae Ho}",
year = "2016",
doi = "10.18632/oncotarget.10432",
language = "English (US)",
volume = "7",
pages = "48562--48576",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "30",

}

TY - JOUR

T1 - Integrated omics-analysis reveals Wnt-mediated NAD+ metabolic reprogramming in cancer stem-like cells

AU - Lee, Jueun

AU - Kee, Hyun Jung

AU - Min, Soonki

AU - Park, Ki Cheong

AU - Park, Sunho

AU - Hwang, Tae Hyun

AU - Ryu, Do Hyun

AU - Hwang, Geum Sook

AU - Cheong, Jae Ho

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Calcium signaling

KW - Cancer stem cells

KW - Integrated analysis

KW - Metabolic reprogramming

KW - Wnt signaling

UR - http://www.scopus.com/inward/record.url?scp=84982832249&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982832249&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.10432

DO - 10.18632/oncotarget.10432

M3 - Article

VL - 7

SP - 48562

EP - 48576

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 30

ER -