Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death due to its late diagnosis that removes the opportunity for surgery and metabolic plasticity that leads to resistance to chemotherapy. Metabolic reprogramming related to glucose, lipid, and amino acid metabolism in PDAC not only enables the cancer to thrive and survive under hypovascular, nutrient-poor and hypoxic microenvironments, but also confers chemoresistance, which contributes to the poor prognosis of PDAC. In this review, we systematically elucidate the mechanism of chemotherapy resistance and the relationship of metabolic programming features with resistance to anticancer drugs in PDAC. Targeting the critical enzymes and/or transporters involved in glucose, lipid, and amino acid metabolism may be a promising approach to overcome chemoresistance in PDAC. Consequently, regulating metabolism could be used as a strategy against PDAC and could improve the prognosis of PDAC.

Keywords: Chemotherapy; Glutamine; Glycolysis; Lipogenesis; Pancreatic cancer.

Fig. 1

The mechanism of chemoresistance in PDAC. The epithelial–mesenchymal transition phenotype, cancer stem cells, the tumor microenvironment and the deregulation of metabolic pathways induced by chemotherapeutic agents, including changes in drug influx and efflux transporters and changes in enzymes that participate in drug effects, contribute to chemoresistance in PDAC. The arrows in black indicate shifts or bioconversion, and the upward and downward arrows in red indicate upregulation and downregulation, respectively. EMT epithelial-mesenchymal transition, CSCs cancer stem cells, TME tumor microenvironment, CAFs cancer-associated fibroblasts, TAMs tissue-associated macrophages, ROS reactive oxygen species, PSCs pancreatic stellate cells

Fig. 2

The pharmacological mechanism and metabolism of gemcitabine in cancer cells. Gemcitabine (dFdC) is transported into the cytoplasm by hENT/hCNT and phosphorylated by dCK, NMPK and NDPK into active forms to terminate DNA synthesis in cancer cells. The arrows in black indicate shifts or bioconversion, and the T-ended stop bar indicates negative regulation. dFdC 2′,2′-difluorodeoxycytidine, gemcitabine, dFdCMP gemcitabine monophosphate, dFdCDP gemcitabine diphosphate, dFdCTP gemcitabine triphosphate, dFdU 2′,2′-difluorodeoxyuridine, dFdUMP 2′,2′-difluorodeoxyuridine monophosphate, CDP cytidine diphosphate, dCDP deoxycytidine diphosphate, dCTP deoxycytidine triphosphate, DCK deoxycytidine kinase, DCTD deoxycytidine monophosphate deaminase, CDA cytidine deaminase, 5′-NT 5′-nucleotidase, RR ribonucleotide reductase, hCNTs concentrative nucleoside transporters, hENTs equilibrative nucleoside transporters

Fig. 3

Overview of reprogrammed glucose, amino acid and lipid metabolism in PDAC. Cancer cells regulate biochemical transporters and enzymes involved in metabolic pathways to survive harsh conditions and highly toxic anticancer drugs, and this regulation can confer chemoresistance in PDAC. The arrows indicate shifts or bioconversion, and the plus and minus symbols in the red circle indicate upregulation and downregulation, respectively. GLUTs glucose transporters, SGLTs sodium-dependent glucose transporters, HK hexokinase, G6P glucose 6-phosphate, GPI phosphohexose isomerase, F6P fructose 6 phosphate, PFK1 phosphofructokinase-1; F1,6BP, fructose 1,6-bisphosphate, ALDO aldolase, TPI triose phosphate isomerase, GA3P glyceraldehyde 3-phosphate, DHAP dihydroxyacetone phosphate, GAPDH glyceraldehyde 3-phosphate dehydrogenase, 1,3-BPG 1,3-bisphosphoglycerate, PGK phosphoglycerate kinase, 3-PG 3-phosphoglycerate, PGM phosphoglycerate mutase, 2-PG 2-phosphoglycerate, ENO enolase, PEP phosphoenolpyruvate, PK pyruvate kinase, LDH lactate dehydrogenase, MCT monocarboxylate transporter, G6PD glucose-6-phosphate dehydrogenase, 6PG 6-phosphogluconate, 6PGD 6-phosphogluconate dehydrogenase, R5P ribose-5-phosphate, NADPH nicotinamide adenine dinucleotide phosphate hydrogen, GFAT glutamine fructose-6-phosphate amidotransferase, GlcN-6P glucosamine 6-phosphate, UDP-GlcNAc uridine 5′-diphospho-N-acetylglucosamine, OGT O-linked N-acetylglucosamine transferase, OGA O-GlcNAcase, PDH pyruvate dehydrogenase, CS citrate synthase, OAA oxaloacetate, TCA tricarboxylic acid, α-KG α-ketoglutarate, ACLY ATP citrate lyase, ACCA acetyl-CoA carboxylase, FASN fatty acid synthase, SCD1, stearoyl-CoA desaturase, SFA saturated fatty acids, PUFA polyunsaturated fatty acids, MUFA monounsaturated fatty acids, HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A, HMGCR 3-hydroxy-3-methylglutaryl coenzyme A reductase, MVA mevalonate, ACAT1 acyl-CoA cholesterol acyltransferase, LDL low-density lipoprotein, LDLR low-density lipoprotein receptor, Gln glutamine, Glu glutamate, Pro proline, Asn asparagine, Asp aspartate, Cys cysteine, Gly glycerine, BCAAs branched chain amino acids, GLS1 glutaminase, GDH glutamate dehydrogenase, GOT glutamic oxaloacetic transaminase, POX proline oxidase, ASNS asparagine synthetase, MDH1 malate dehydrogenase, MEI1 malic enzyme, GSH reduced glutathione, GSSG oxidized glutathione