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.

Cancer stem cells (CSCs): metabolic strategies for their identification and eradication

“…For instance, it has been recently demonstrated that some pluripotency genes like NANOG trigger CSC maintenance and promote tumorigenicity in vivo by inducing a functional reprogramming of mitochondrial metabolism in HCC [ 116 ]. Lee et al [ 117 ] recently shaped the oncometabolites and transcriptomic profile of breast cancer stem-like cells, and found that the Wnt pathway regulates nicotinic acid adenine dinucleotide phosphate (NAADP) levels, which in turn promote CSC survival. In addition, non-codifying genomic sequences may be implicated in CSC action, as demonstrated by the evidence that an miR-122-mediated regulation of the glycolytic enzyme PK4 inhibits stem phenotypes in CD133 (+) HCC cells [ 118 ].…”

Survival of Cancer Stem-Like Cells Under Metabolic Stress via CaMK2α-mediated Upregulation of Sarco/Endoplasmic Reticulum Calcium ATPase Expression

“…Previously, we demonstrated that chronic metabolic stress induced the emergence of CSCs through reprogrammed Wnt signaling (5). Notably, these CSCs exhibited resistance to glucose deprivation-induced apoptosis by altering NAD þ metabolism, which is mechanistically related to Ca 2þ signaling (6).…”

Mitochondria-centric bioenergetic characteristics in cancer stem-like cells

“…OXPHOS inhibitors are emerging as promising therapeutics of malignant cancers marked by increased mitochondrial respiration (Wolf 2014 ). Antidiabetic biguanides, metformin and phenformin, have been rediscovered as OXPHOS inhibitors, and their anti-cancer effects have been proven in epidemiological, preclinical, and clinical studies (Lee et al 2016c ). Notably, metformin demonstrated selective efficacy against CSCs, sensitizing them to conventional treatments (Hirsch et al 2009 ).…”