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  • br PEPCK This enzyme decarboxylates and then phosphorylates


    PEPCK This enzyme decarboxylates and then phosphorylates oxaloacetate to form phosphoenolpyruvate (PEP) in the second step of gluconeogenesis after the carboxylation of pyruvate catalyzed by PC. PEPCK1 (PEPCK-C, encoded by the PCK1 gene) and PEPCK2 (PEPCK-M, encoded by the PCK2 gene) are two isoforms distributed in the cytosol and mitochondria, respectively. Although the function of PEPCK has been linked almost exclusively to gluconeogenesis, the major function of PEPCK is in cataplerosis [12]. By converting oxaloacetate to PEP, PEPCK allows the use of non-carbohydrate sources (glutamine, lactate, and TCA cycle intermediates) under nutrient starvation 9, 13. On the other hand, PEPCK serve as a feeder reaction to provide carbon for gluconeogenesis and ultimately several downstream anabolic pathways (glyceroneogenesis, serine synthesis, and the PPP) (Figure 1). In fact, any compound that enters the TCA cycle can be utilized via its cataplerotic function for anabolic synthesis [14]. Tumors hijack PEPCK to engage truncated gluconeogenesis as an adaptive response to nutrient stress. Hence, aberrant expression of PEPCK isoforms occurs in many types of cancers. PEPCK1 is overexpressed in colorectal cancer and melanoma, and PEPCK2 is overexpressed in cancers of the lung, prostate, thyroid, bladder, breast, and TAK-875 7, 8, 15, 16, 17. However, in gluconeogenic tissues such as the liver and kidney, PEPCK acts as a tumor suppressor because it facilitates severe cataplerosis to generate glucose, thus hindering both glycolysis and the TCA cycle, and breaking energy homeostasis. Loss of PEPCK1/2 is observed in hepatocellular carcinoma (HCC) and clear cell renal cell carcinoma (ccRCC) 18, 19.
    FBPase FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis. Humans have two isoforms of FBPase, FBP1 (L-FBP) and FBP2 (M-FBP). FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle [45]. Because FBPase acts as a tumor suppressor to enhance OXPHOS and ROS levels that are detrimental to cancer cells, loss of FBP1 or FBP2 contributes to the initiation, promotion, and progression of multiple cancers, including basal-like breast cancer (BLBC) [11], pancreatic ductal adenocarcinoma (PDAC) [46], ccRCC 10, 47, HCC [48], colon cancer [31], gastric cancer [49], lung cancer [50], cervical carcinoma [51], and melanoma 32, 52.
    G6Pase G6Pase hydrolyzes glucose-6-phosphate (G-6-P) into free glucose in the terminal step of gluconeogenesis and glycogenolysis. This hydrolytic reaction stems from the G6Pase complex, comprising the glucose-6-phosphatase catalytic subunit (G6PC) and the glucose-6-phosphate translocase (G6PT), that are coupled functionally, rather than physically. G6PT transports G-6-P from the cytoplasm into the ER lumen, where G-6-P is hydrolyzed by G6PC. Deficiency in G6PC or G6PT disrupts this process and causes a severe metabolic disease known as glycogen storage disease type I (GSD-I). GSD-I is characterized by impaired blood glucose homeostasis and risk for developing hepatocellular adenoma and carcinoma 81, 82. Similarly to PEPCK, G6Pase is absent in gluconeogenic tissue tumors such as HCC and renal cell carcinoma [33], while G6Pase is overexpressed in non-gluconeogenic tissue tumors such as ovarian cancer and glioblastoma 83, 84.
    Concluding Remarks Metabolic heterogeneity, compensatory effects, and the tumor microenvironment pose considerable challenges to metabolic therapies (Box 1). Therefore, metabolic drug combinations may be used effectively to induce synthetic lethality in which two drugs cause cell death in combination but not individually 97, 98. Immunotherapy could be combined with metabolic therapy because metabolic rewiring also occurs in T lymphocytes upon their activation, paralleling changes taking place in tumor cells, which results in immune and cancer cells competing for nutrients 43, 99. In addition to T cells, as noted above, key gluconeogenic enzymes also have diverse effects on other cells in the tumor environment such as NK cells, monocytes, fibroblasts, and endothelial cells. Whether targeting gluconeogenesis can affect the immune response or tumor microenvironment requires extensive studies 43, 44, 78, 79, 96. Overall, gluconeogenesis and its key enzymes have the potential to become prognostic markers and druggable targets in clinical applications. Several issues central to the development of these therapeutic strategies remain open, such as the contrasting effects of key gluconeogenic enzymes in different cancers or in different conditions. Further studies on the role of these key enzymes in cancer will lead to more selective and efficient anticancer effects.