Abstract
SummaryLipid droplets, which store triglycerides and cholesterol esters, are a prominent feature of clear cell renal cell carcinoma (ccRCC). Although their presence in ccRCC is critical for sustained tumorigenesis, their contribution to lipid homeostasis and tumor cell viability is incompletely understood. Here we show that disrupting triglyceride synthesis compromises the growth of both ccRCC tumors and ccRCC cells exposed to tumor-like conditions. Functionally, hypoxia leads to increased fatty acid saturation through inhibition of the oxygen-dependent stearoyl-CoA desaturase (SCD) enzyme. Triglycerides counter a toxic buildup of saturated lipids, primarily by releasing the unsaturated fatty acid oleate (the principal product of SCD activity) from lipid droplets into phospholipid pools. Disrupting this process derails lipid homeostasis, causing overproduction of toxic saturated ceramides and acyl-carnitines as well as activation of the NF-κB transcription factor. Our work demonstrates that triglycerides promote homeostasis by “buffering” specific fatty acids.
Highlights
Proliferating cancer cells exhibit an increased dependence on biosynthetic intermediates (Vander Heiden and DeBerardinis, 2017), including fatty acids (FAs) that support the construction of organelle and plasma membranes
Disruption of TG Synthesis Compromises clear cell renal cell carcinoma (ccRCC) Tumor Growth the functional roles of CEs in cancer have been interrogated to some extent (Yue et al, 2014), TGs have so far remained considerably less well studied
DGATs appear to carry out mutually redundant functions in the storage of both endogenously synthesized and exogenously derived FAs (Figure 1A)
Summary
Proliferating cancer cells exhibit an increased dependence on biosynthetic intermediates (Vander Heiden and DeBerardinis, 2017), including fatty acids (FAs) that support the construction of organelle and plasma membranes. The product of FASN enzymatic activity, can be further modified by elongation and desaturation, where double bonds between carbon atoms are introduced into long-chain FAs. Stearoyl-coenzyme A (CoA) desaturase (SCD), the principal enzyme responsible for desaturation, is critical for sustained viability of a variety of tumor cell types (Igal, 2016). Clearly important for cell survival, activity of the oxygen (O2)-dependent SCD enzyme can be constrained by tumor hypoxia (Figure 1A). Saturated FA-induced toxicity can be alleviated by supplying exogenous unsaturated lipids (for instance, by increasing the availability of serum FAs), indicating that lipid uptake is an important mechanism for maintaining homeostasis in hypoxic cancer cells (Young et al, 2013)
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