Serine Restriction Alters Sphingolipid Synthesis to Lower Tumor Growth

Deprivation of nonessential amino acids such as serine may be a useful strategy for restricting tumor progression, and serine depletion can cause the de novo sphingolipid-biosynthesis enzyme serine palmitoyltransferase (SPT) to use alanine as a substrate, producing noncanonical 1-deoxysphingolipids. Muthusamy and colleagues found that increased alanine levels or reduced serine levels hindered the growth of colorectal cancer spheroids. In anchorage-independent colorectal cancer cultures, inhibition or knockdown of mitochondrial pyruvate carrier (MPC), the expression of which is low in colon cancer, resulted in decreased alanine levels; further, MPC inhibition or knockdown increased colorectal cancer spheroid growth, and MPC inhibition increased serine levels in colorectal cancer spheroids. Colorectal cancer spheroids grown in serine-depleted medium had increased levels of 1-deoxysphinganine, and knockdown of the genes encoding either of the two MPC subunits reduced 1-deoxysphinganine levels. Additionally, inhibition of SPT increased colorectal cancer spheroid growth. Inhibition of ceramide synthases—which convert 1-deoxysphinganine into toxic 1-deoxydihydroceramide—promoted colorectal cancer spheroid growth. Colorectal cancer spheroids grown in serine- and glycine-free medium had increased levels of toxic 1-deoxydihydroceramide, but inhibition of SPT or MPC prevented this effect. In xenograft experiments, colorectal cancer growth was inhibited in mice fed a serine- and glycine-free diet compared with mice fed an isonitrogenous control diet, and tumors from mice fed the serine- and glycine-free diet had five- to eightfold increases in 1-deoxysphinganine, 1-deoxydihydroceramide, and 1-deoxyceramide (a product of 1-deoxydihydroceramide). Alanine supplementation had no additional antitumor effects, perhaps because of an observed increase in expression of alanine transaminases in the liver. Additional xenograft experiments showed that SPT inhibition in mice fed diets low in serine and glycine increased tumor growth and decreased levels of 1-deoxydihydroceramide and 1-deoxyceramide in tumors. Further, inhibition of phosphoglycerate dehydrogenase to decrease serine synthesis in mice fed a normal diet reduced serine and glycine levels in tumors and plasma, decreased tumor size, and caused deoxysphingolipid accumulation in tumors. Collectively, these findings provide deep mechanistic insight into the antitumor effects of serine restriction and its effects on lipid biosynthesis in cancer.

Muthusamy T, Cordes T, Handzlik MK, You L, Lim EW, Gengatharan J, et al. Serine restriction alters sphingolipid diversity to constrain tumour growth. Nature 2020 Aug 12 [Epub ahead of print].

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