Therapeutic targets in cancer cell metabolism and autophagy

Abstract

The metabolism of cancer cells is reprogrammed both by oncogene signaling and by dysregulation of metabolic enzymes. The resulting altered metabolism supports cellular proliferation and survival but leaves cancer cells dependent on a continuous supply of nutrients. Thus, many metabolic enzymes have become targets for new cancer therapies. Recently, two processes—expression of specific isoforms of metabolic enzymes and autophagy—have been shown to be crucial for the adaptation of tumor cells to changes in nutrient availability. An increasing number of approved and experimental therapeutics target these two processes. A better understanding of the molecular basis of cancer-associated metabolic changes may lead to improved cancer therapies.

Figure 1. Core metabolic pathways and metabolic enzymes suitable as cancer therapeutic targets

Active metabolic pathways in proliferating cells involving glucose and glutamine catabolism are interconnected and linked to macromolecular synthesis and energy balance. Key metabolic enzymes discussed in the text (shown in blue) are actively investigated as therapeutic targets for cancer treatment. Metabolic enzymes targeted by registered agents are shown in Red. ACL, ATP citrate lyase; αKG, α-ketoglutarate; DHFR, dehydrofolate reductase;; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; F-2,6-BP, fructose-2,6-bisphosphate; F6P, fructose-6-phosphate; FBP, fructose-1,6-bisphosphate; FH, fumarate hydratase; G6P, glucose-6-phosphate; GLS, glutaminase; HK2, hexokinase 2; IDH, isocitrate dehydrogenase; LDHA, lactate dehydrogenase A; MCT1,4, monocarboxylate transporter 1,4; OAA, oxaloacetate; PDH, pyruvate dehydrogenase complex; PDK, pyruvate dehydrogenase kinase; PEP, phosphoenolpyruvate; PFK1, phosphofructokinase 1; PFK2, phosphofructokinase 2; PGAM, phosphoglycerate mutase; PHGDH, phosphoglycerate dehydrogenase; PKM2, pyruvate kinase M2 isoform; R5P, ribose-5-phosphate; SDH, succinate dehydrogenase; THF, tetrahydrofolate; TYMS, thymidylate synthase

Figure 2. Modulators of the autophagy pathway

Various growth and nutrient signaling pathways are associated with regulation of autophagy. Following inhibition of mTOR, the ULK/Atg13/FIP200 complex is activated and initiate autophagosome/phagophore formation. The class III PI3 kinase (Vps34)-Atg14L-Beclin 1 complex also regulates the autophagosome nucleation step. To expand the autophagosome membrane, two ubiquitin-like conjugation systems are required for conjugation of LC3 and Atg12 to phosphatidyl ethanolamine (PE) on the autophagosome membrane and Atg5, respectively. Further, the Atg12-Atg5 conjugate interacts with Atg16, presumably located on the surface of the autophagosome membrane. The complete autophagosome fuse with the lysosome to form the autolysosome and cargo molecules enwrapped by autophagosomes are degraded by lysosomal hydrolases and recycled back to the cytoplasm. As shown in red, a variety of pharmacological inhibitors are depicted which modulate distinct steps of autophagy. Some autophagy proteins which enzymatic activity (shown in green and yellow) could be crucial target proteins for modulation of autophagy activity. Potential points where inhibitors could be potentially developed are shown in blank boxes.