GOT2: New therapeutic target in pancreatic cancer

Abstract

In recent years, the incidence and mortality rates of pancreatic cancer have been steadily increasing, and conventional therapies have shown a high degree of tolerance. Therefore, the search for new therapeutic targets remains a key issue in current research. Mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) is an important component of the malate-aspartate shuttle system, which plays an important role in the maintenance of cellular redox balance and amino acid metabolism, and has the potential to become a promising target for anti-cancer therapy. In this paper, we will elaborate on the metabolic and immune effects of GOT2 in pancreatic cancer based on existing studies, with a view to opening up new avenues for the treatment of pancreatic cancer.

Keywords: GOT2; Glutamine metabolism; PPARδ; Pancreatic cancer; Tumor microenvironment.

Figure 1

Metabolic and immune functions of GOT2 in pancreatic cancer cells. First, GOT2 catalyzes transamination reaction in mitochondria, and the products can directly promote cell proliferation. Aspartate provides raw materials for protein and nucleotide synthesis, and oxaloacetate participates in the TCA cycle. Second, GOT2 is a key component of the malate-aspartate shuttle system, which maintains cellular redox balance. In addition, pancreatic cancer cells exhibit unique glutamine metabolism. On this basis, decreased SIRT3 expression leads to an increased level of GOT2 acetylation. The acetylation of GOT2 at 3K sites enhances the protein association of GOT2-MDH2, which promotes the malate-aspartate NADH shuttle activity to increase ATP production and stimulates NADPH production to inhibit ROS, thereby reducing the expression of cyclin-dependent kinase inhibitor p27 and suppressing cellular senescence (leftmost plot). An unexpected nuclear role of GOT2 in pancreatic cancer: As a nuclear fatty acid transporter, GOT2 promotes the transcriptional activity of PPARδ by directly binding to fatty acids (mainly arachidonic acid) and induces the expression of immunomodulatory target genes. PTGS2 encodes COX2 that inhibits T cell-mediated anti-tumor immunity. CSF1 and REG3G encodes secretory protein which recruits myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment (right plot). OAA, oxaloacetate; α-KG, α-ketoglutarate; Ara, arachidonic acid; Asp, aspartate; COX2, cyclooxygenase 2; CSF1, colony stimulating factor 1; Glu, glutamine; Gln, glutamine; GOT2, glutamic-oxaloacetic transaminase 2; Mal, malate; MDH2, malate dehydrogenase 2; PPARδ, peroxisome proliferator-activated receptor δ; PTGS2, prostaglandin endoperoxide synthase 2; Pyr, pyruvate; REG3G, regenerating islet-derived protein 3 gamma; ROS, reactive oxygen species; SIRT3, sirtuin-3; TCA, tricarboxylic acid. This picture was drawn by Figdraw.

Figure 2

Alternative mechanisms bypass GOT2 silencing in pancreatic cancer cells. CAFs can secrete pyruvate in the pancreatic tumor microenvironment. Here pyruvate is transported to pancreatic cancer cells via MCT1 and converted into lactate, which can restore the redox imbalance caused by GOT2 loss and reverse the GOT1 pathway to synthesize Asp, thus saving pancreatic cancer cell proliferation in vitro. Under hypoxia conditions, HIF1A enhances the effect of macropinocytosis by inducing CA9 expression. Macropinocytosis can directly provide enough Asp to GOT2-deficient pancreatic cancer cells by capturing environmental albumin and releasing amino acids inside the cells. These two alternative routes for acquiring Asp allow pancreatic cancer to bypass the metabolic limitations from GOT2 loss. Asp, aspartate; CA9, carbonic anhydrase IX; CAFs, cancer-associated fibroblasts; GOT1/2, glutamic-oxaloacetic transaminase 1/2; HIF1A, hypoxia-inducible factor 1 subunit α; MCT1, monocarboxylate transporter 1; Pyr, pyruvate. This picture was drawn by Figdraw.