Serine restriction alters sphingolipid diversity to constrain tumour growth

Abstract

Summary Serine, glycine, and other non-essential amino acids are critical for tumor progression, and strategies to limit their availability are emerging as potential cancer therapies 1 – 3 . However, the molecular mechanisms driving this response remain unclear, and the impact on lipid metabolism is relatively unexplored. Serine palmitoyltransferase (SPT) catalyzes the de novo biosynthesis of sphingolipids but also produces non-canonical 1-deoxysphingolipids (doxSLs) when using alanine as a substrate 4 , 5 . DoxSLs accumulate in the context of SPTLC1 or SPTLC2 mutations 6 , 7 or low serine availability 8 , 9 to drive neuropathy, and deoxysphinganine (doxSA) has been investigated as an anti-cancer agent 10 . Here we exploit amino acid metabolism and SPT promiscuity to modulate the endogenous synthesis of toxic doxSLs and slow tumor progression. Anchorage-independent growth reprograms a metabolic network involving serine, alanine, and pyruvate resulting in increased susceptibility to endogenous doxSL synthesis. Targeting the mitochondrial pyruvate carrier (MPC) promotes alanine oxidation to mitigate doxSL synthesis and improves spheroid growth, while direct inhibition of doxSL synthesis drives similar phenotypes. Restriction of dietary serine/glycine potently induces accumulation of doxSLs in xenografts while decreasing tumor growth. Pharmacological modulation of SPT rescues xenograft growth on serine/glycine-restricted diets, while reduction of circulating serine by inhibition of phosphoglycerate dehydrogenase (PHGDH) leads to doxSL accumulation and mitigates tumor growth. SPT promiscuity therefore links serine and mitochondrial alanine metabolism to membrane lipid diversity, which sensitizes tumors to metabolic stress.

Lysine Deprivation Induces AKT-AADAT Signaling and Overcomes EGFR-TKIs Resistance in EGFR-Mutant Non-Small Cell Lung Cancer Cells

“…In the present study, we found that the afatinib-resistant subline (PC9-AR-C3) ( Figure 2 A, Figures S2 and S3 ) and osimertinib-resistant sublines (PC9-OR-D4 and PC9-OR-E8) ( Figure 2 B, Figures S4 and S5 ) were sensitive to the short-term depletion of lysine ( Figure 3 ). Several recent studies have suggested that a diet involving the restriction of specific amino acids could be used against particular types of cancer to precisely reduce the rate of tumor growth and metastasis [ 33 , 34 ]. In addition, recent research using patient-derived xenograft (PDX) models demonstrated that the manipulation of dietary methionine restriction might be a strategy to improve the outcomes of therapy for colorectal cancer [ 35 ].…”

Metabolic Reprogramming of Cancer Cells during Tumor Progression and Metastasis

“…Regarding the amino acid metabolism required for anchorage-independent tumor growth, apart from anaplerosis and reductive carboxylation of glutamine, tumor spheroids show increased alanine secretion compared to adherent cells [ 117 ]. Decreasing alanine secretion by genetical or pharmacological inhibition of mitochondrial pyruvate carrier enhanced spheroid growth and increased serine synthesis, while alanine supplementation had the opposite effect.…”

“…Decreasing alanine secretion by genetical or pharmacological inhibition of mitochondrial pyruvate carrier enhanced spheroid growth and increased serine synthesis, while alanine supplementation had the opposite effect. It was thus suggested that a balance between alanine and serine may regulate spheroid viability through altered sphingolipid diversity ( Figure 5 ) [ 117 ].…”

Kicking off sphingolipid biosynthesis: structures of the serine palmitoyltransferase complex

“…Moreover, these structures may guide the design of inhibitors and activators of SPT as potential therapeutics, where either positive, as suggested for the treatment of asthma 22 , or negative regulation, for example in hepatic steatosis 23 , may have benefit. More speculatively, small molecule modulators could be produced that allosterically repair the enzyme defects in HSAN1 or, provocatively, increase deoxysphingolipid synthesis as an anticancer therapeutic strategy 24 . These structures have clearly set the stage for a deeper understanding of the regulated production of the idiosyncratic but essential sphingolipids.…”