The role of serine metabolism in lung cancer: From oncogenesis to tumor treatment

Abstract

Metabolic reprogramming is an important hallmark of malignant tumors. Serine is a non-essential amino acid involved in cell proliferation. Serine metabolism, especially the de novo serine synthesis pathway, forms a metabolic network with glycolysis, folate cycle, and one-carbon metabolism, which is essential for rapidly proliferating cells. Owing to the rapid development in metabolomics, abnormal serine metabolism may serve as a biomarker for the early diagnosis and pathological typing of tumors. Targeting serine metabolism also plays an essential role in precision and personalized cancer therapy. This article is a systematic review of de novo serine biosynthesis and the link between serine and folate metabolism in tumorigenesis, particularly in lung cancer. In addition, we discuss the potential of serine metabolism to improve tumor treatment.

Keywords: PHGDH; PSAT1; PSPH; lung cancer; serine metabolism.

FIGURE 1

De novo serine synthesis pathway and its regulator. 3-PG is converted to serine by PHGDH, PSAT1, and PSPH. Serine is then converted to glycine by SHMT. 3-PG: 3-phosphoglycerate; 3-PP: 3-phosphohydroxypyruvate; 3-PS: 3-phosphoserine; PHGDH: 3-phosphoglycerate dehydrogenase; PSAT1: phosphoserine aminotransferase; PSPH: phosphoserine phosphatase; SHMT: serine hydroxymethyl transferase; Ser: serine; Gly: glycine; Glu: glutamate. IKKε: IκB Kinase ε; ATF3: activating transcription factor 3; NRF2: NFE2 like bZIP transcription factor 2; ATF4: activating transcription factor 4.

FIGURE 2

SSP and one-carbon metabolism. During the conversion of serine to glycine, a methylene group breaks off from serine and enters the folate cycle. Ultimately, this 1C unit acts as a methyl donor in the form of a SAM. 3-PG: 3-phosphoglycerate; SHMT: serine hydroxymethyl transferase; Ser: serine; Gly: glycine; THF: tetrahydrofolate; Met: methionine; SAM: S-adenosyl methionine; SAH: S-adenosyl-L-homocysteine; Hcy: homocysteine.

FIGURE 3

Protein interactions of SSP core enzymes and their effect on patient’s overall survival (A) Protein interactions of SSP core enzymes. We retrieved PHGDH, PSAT1, PSPH, SHMT1 and SHMT2 on STRING (https://cn.string-db.org/) and choose Homo sapiens to get the protein interaction network of SSP key enzymes in human cells. (B) SSP core enzyme’s function influences patient survival rates in lung cancer. The prognostic value of PHGDH, PSAT1, PSPH, SHMT1 and SHMT2 expression was analyzed using Kaplan-Meier Plotter (http://kmplot.com/analysis/). The results showed that the overall survival of patients with high expression of PHGDH, PSAT1, SHMT1 and SHMT2 was significantly decreased.