期刊
ONCOTARGET
卷 7, 期 30, 页码 48562-48576出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10432
关键词
calcium signaling; cancer stem cells; integrated analysis; metabolic reprogramming; Wnt signaling
资金
- Korean Health Technology R&D Project through the Korean Health Industry Development Institute (KHIDI)
- Ministry of Health & Welfare, Republic of Korea [HI13C2162]
- National Research Foundation of Korea (NRF) grant - Korean government (MSIP) [NRF-2011-0030086]
- National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning, Korea [2013M3A9B6046418, NRF-2015M3A6A4076702]
- National Research Council of Science and Technology [DRC-14-3-KBSI]
- National Research Foundation of Korea [2015M3A6A4076702] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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