Cristoforo Grasso, Gerrit Jansen, Elisa Giovannetti

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Drug resistance in pancreatic cancer: Impact of altered energy metabolism Cristoforo Grasso, Gerrit Jansen, Elisa Giovannetti Critical Reviews in Oncology / Hematology Volume 114, Pages 139-152 (June 2017) DOI: 10.1016/j.critrevonc.2017.03.026 Copyright © 2017 Elsevier B.V. Terms and Conditions

Fig. 1 Summary of pancreatic cancer metabolic reprogramming. Metabolic reprogramming is characterized by enhanced glycolysis, PPP, glutaminolysis, among others. These pathways provide cancer cells with not only essential energy but also important precursors to supply large-scale biosynthesis, rapid proliferation, growth, invasion, metastasis, and resistance to anti-cancer therapies. Abbreviations: AMPK: AMP-activated protein kinase; HK2: hexokinase 2; LDHA, lactate dehydrogenase A; GLS1: glutaminase; GLUD, glutamate dehydrogenase; GOT1, cytosolic aspartate transaminase; HIF1-a: Hypoxia-inducible factor 1-alpha; KRAS: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; MCT: monocarboxylic acid transporter; mTOR: mammalian target of rapamycin; PK: pyruvate kinase PDH, pyruvate dehydrogenase; PDK: pyruvate dehydrogenase kinase; PPP: pentose phosphate pathway; RRM1: Ribonucleoside-diphosphate reductase large subunit; SLC1A5: Neutral amino acid transporter B(0); TCA: tricarboxylic acid cycle. Critical Reviews in Oncology / Hematology 2017 114, 139-152DOI: (10.1016/j.critrevonc.2017.03.026) Copyright © 2017 Elsevier B.V. Terms and Conditions

Fig. 2 KRAS enhance non-canonical pathway of glutamine metabolism in pancreatic cancer. In KRAS-mutant pancreatic cancer, mitochondrial glutamine flux is rewired to principally flux through GOT2, rather of the canonical GLUD1 pathway. Abbreviations: GOT2: mitochondrial aspartate transaminase; GLUD1: glutamate dehydrogenase 1; Asp: aspartate; ME1: malic enzyme 1; ME2: malic enzyme 2; GLS1: glutaminase 1; MDH1: malate dehydrogenase 1; GOT1: cytosolic aspartate transaminase; OAA: oxaloacetate; αKG: α-ketoglutarate; TCA: tricarboxylic acid cycle. Critical Reviews in Oncology / Hematology 2017 114, 139-152DOI: (10.1016/j.critrevonc.2017.03.026) Copyright © 2017 Elsevier B.V. Terms and Conditions

Fig. 3 Hypoxic and nutrient starvation in pancreatic tumor development. On the left, normal pancreas with functional pancreatic ducts and blood vessels. On the right, pancreatic tumor cells are surrounded by a dense stroma constituted by nerve fibers, immune cells, occluded blood vessels, cancer associated fibroblasts. Such desmoplasic reaction gradually reduces oxygen and nutrient supply to pancreatic cancer cells. Critical Reviews in Oncology / Hematology 2017 114, 139-152DOI: (10.1016/j.critrevonc.2017.03.026) Copyright © 2017 Elsevier B.V. Terms and Conditions

Fig. 4 Schematic representation of the processes related to Warburg effect. Critical Reviews in Oncology / Hematology 2017 114, 139-152DOI: (10.1016/j.critrevonc.2017.03.026) Copyright © 2017 Elsevier B.V. Terms and Conditions