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.
Highlights
Malignant progression requires coordinated adaptation of cellular metabolism that alters the physiology of transformed cells providing selective advantages [1]
NAAD+ increases in chronic metabolic stress induced stem-like cancer cells
We hypothesized that cancer stem-like cells (CSCs) could have undergone a metabolic reprogramming associated with anti-apoptotic capability upon chronic metabolic stress arising from glucose deprivation
Summary
Malignant progression requires coordinated adaptation of cellular metabolism that alters the physiology of transformed cells providing selective advantages [1]. In the tumor metabolic microenvironment, which is continuously reshaped during tumor progression and provides selective pressure, tumor cells can acquire adaptive characteristics, including resistance to apoptosis, invasion, and metastasis [2,3,4]. These acquired phenotypes share characteristics with tumor initiating cells or cancer stem-like cells (CSCs). Comprehensive understanding of molecular physiology of CSCs is indispensible for developing promising anticancer strategy
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