Linking Serine/Glycine Metabolism to Radiotherapy Resistance

Abstract

The activation of de novo serine/glycine biosynthesis in a subset of tumors has been described as a major contributor to tumor pathogenesis, poor outcome, and treatment resistance. Amplifications and mutations of de novo serine/glycine biosynthesis enzymes can trigger pathway activation; however, a large group of cancers displays serine/glycine pathway overexpression induced by oncogenic drivers and unknown regulatory mechanisms. A better understanding of the regulatory network of de novo serine/glycine biosynthesis activation in cancer might be essential to unveil opportunities to target tumor heterogeneity and therapy resistance. In the current review, we describe how the activation of de novo serine/glycine biosynthesis in cancer is linked to treatment resistance and its implications in the clinic. To our knowledge, only a few studies have identified this pathway as metabolic reprogramming of cancer cells in response to radiation therapy. We propose an important contribution of de novo serine/glycine biosynthesis pathway activation to radioresistance by being involved in cancer cell viability and proliferation, maintenance of cancer stem cells (CSCs), and redox homeostasis under hypoxia and nutrient-deprived conditions. Current approaches for inhibition of the de novo serine/glycine biosynthesis pathway provide new opportunities for therapeutic intervention, which in combination with radiotherapy might be a promising strategy for tumor control and ultimately eradication. Further research is needed to gain molecular and mechanistic insight into the activation of this pathway in response to radiation therapy and to design sophisticated stratification methods to select patients that might benefit from serine/glycine metabolism-targeted therapies in combination with radiotherapy.

Keywords: DNA repair; PHGDH; PSAT1; PSPH; SHMT; cancer; hypoxia; radiotherapy; redox homeostasis; resistance; serine and glycine metabolism.

Figure 1

Overview of serine/glycine biosynthesis pathway activation in cancer. Serine/glycine biosynthesis pathway branches from the glycolysis, in which the intermediate 3P-glycerate is converted into serine and glycine after a chain of consecutive enzymatic reactions controlled by PHGDH, PSAT, PSPH, and SHMT1/2 enzymes. Cancer cells are characterized by activation of de novo serine/glycine biosynthesis to meet their high biosynthetic and energetic requirements. Activation of de novo serine/glycine biosynthesis and one-carbon (1C) metabolism promote purine and pyrimidine synthesis and supports lipid metabolism, as well as produces reductive equivalents to control redox homeostasis and α-ketoglutarate and S-adenosyl methionine (SAM) to regulate DNA and histone methylation. This representation shows the reduction of glutathione disulfide (GSSC) to glutathione (GSH), which is a tripeptide thiol antioxidant, composed of glycine, cysteine, and glutamic acid, and one of the main regulators of reactive oxygen species (ROS).

Figure 2

Serine/glycine biosynthesis pathway hyperactivation signatures in cancer. Representation of the frequency of distinct alterations in serine/glycine biosynthesis genes, i.e., PHGDH, PSAT1, PSPH, SHMT1, and SHMT2, across a set of patients for different cancer types. These alterations include mRNA overexpression, somatic mutations, and copy number gain/amplification, which can be associated with serine/glycine biosynthesis pathway hyperactivation signature. The graphs also show the frequencies of mRNA overexpression and mutations/copy number variations separately in each case. This data was collected from the The Cancer Genomic Atlas (TCGA) PanCancer Atlas datasets in cBioPortal.org (data collection July 2020).

Figure 3

Serine/glycine biosynthesis pathway activation in tumor treatment resistance. The response to targeted therapies in tumors with abnormal activation of RAS–RAF–MEK–ERK pathway has been associated with increased expression of serine/glycine biosynthesis genes, which might be induced by oncogenic drivers such as EGFR^L858R and KRAS^G12D via ATF4 and NFR2, respectively. In addition, serine/glycine biosynthesis pathway hyperactivation has been linked to the resistance to chemotherapeutic drugs, e.g., doxorubicin, carboplatin, pemetrexed, or 5-fluorouracil in breast, lung, and colorectal cancer (CRC), the proteasome inhibitor bortezomib in multiple myeloma, as well as HIF2α antagonists in renal cell carcinoma.

Figure 4

Linking radiotherapy resistance and serine/glycine metabolism in the tumor and associated tumor microenvironment. Activation of de novo serine/glycine biosynthesis pathway in cancer stem cells (CSC) under hypoxia and nutrient-deprived conditions is important to sustain cancer cell viability and proliferation, supporting the synthesis of nucleotides for DNA repair, as well as the synthesis of reductive equivalents that protect the cancer stem cells and their progeny against redox stress via autocrine and paracrine routes. In addition, de novo serine/glycine biosynthesis enzymes, i.e., PHGDH and PSAT1, are involved in the maintenance of CSCs stemness and self-renewal, for instance, via posttranslational regulation of OCT4, as well as regulating stem cell fate via αKG. In the tumor microenvironment, high PHGDH activity is essential for the survival of endothelial cells and promotes an immunosuppressive microenvironment with an increase in M2 macrophage polarization. In addition, serine and glycine are required for the expression of the pro-inflammatory cytokine IL-1β.

Figure 5

Future perspectives overview implicating serine/glycine metabolism-targeted therapies in combination with radiation therapy. The rational integration of serine/glycine metabolism-targeted therapies in combination with radiotherapy is important to optimize the efficacy and enhance the therapeutic ratio of radiotherapy. The stratification methods to select patients that might benefit from these combined treatment modalities could include the analysis of serine, GSH, or methionine serum levels or the expression of de novo serine/glycine biosynthesis enzymes. The therapeutic strategies targeting serine/glycine metabolism include limiting the availability of exogenous serine by diet restriction and targeting the enzymes of de novo serine/glycine biosynthesis pathways, for instance, SHMT inhibition using sertraline. In addition, mitochondrial inhibitors, e.g., metformin, phenformin or artemether, might have synergistic antitumor effects in combination with serine/glycine-targeted strategies and enhance the response to radiotherapy. Finally, targeting serine/glycine metabolism before radiotherapy, concomitantly or sequentially, requires considering serine/glycine metabolism functions in cancer cells and the tumor microenvironment and how targeting this metabolic pathway might enhance or counteract the response to radiotherapy. The blue arrows indicate expected cellular changes, in green beneficial outcome of the cellular changes and in orange the limitations of the outcomes related to the cellular changes.