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Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited
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Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited
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Journal Article
Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited
2022
Overview
Production of oxidized biomass, which requires regeneration of the cofactor NAD
+
, can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD
+
deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD
+
consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD
+
is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD
+
availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD
+
consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia.
Production of oxidized biomass is necessary to support cancer cell proliferation. In this work, Li et al. provide a quantitative analysis of the cellular needs and biochemical bottlenecks in lipid biosynthesis arising from the requirement to regenerate the cofactor NAD
+
.
