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Study Shows Why Many Cancer Cells Need to Import Fat
- panabee 4y agoArticle TLDR: Cancer cells often grow in hypoxic (oxygen-deficient) environments. The researchers discovered that oxygen is a limiting factor on the biosynthesis of fat molecules, which are essential for creating cells and driving cancer growth. As a result, cancer cells are often dependent on importing fat molecules from their environment since hypoxic conditions throttle lipid generation. This vulnerability offers potential avenues for therapy. Paper Abstract: 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. Paper URL: https://www.nature.com/articles/s42255-022-00588-8 https://www.nature.com/articles/s42255-022-00588-8