Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets

Abstract

Aberrant metabolism is a major hallmark of cancer. Abnormal cancer metabolism, such as aerobic glycolysis and increased anabolic pathways, has important roles in tumorigenesis, metastasis, drug resistance, and cancer stem cells. Well-known oncogenic signaling pathways, such as phosphoinositide 3-kinase (PI3K)/AKT, Myc, and Hippo pathway, mediate metabolic gene expression and increase metabolic enzyme activities. Vice versa, deregulated metabolic pathways contribute to defects in cellular signal transduction pathways, which in turn provide energy, building blocks, and redox potentials for unrestrained cancer cell proliferation. Studies and clinical trials are being performed that focus on the inhibition of metabolic enzymes by small molecules or dietary interventions (e.g., fasting, calorie restriction, and intermittent fasting). Similar to genetic heterogeneity, the metabolic phenotypes of cancers are highly heterogeneous. This heterogeneity results from diverse cues in the tumor microenvironment and genetic mutations. Hence, overcoming metabolic plasticity is an important goal of modern cancer therapeutics. This review highlights recent findings on the metabolic phenotypes of cancer and elucidates the interactions between signal transduction pathways and metabolic pathways. We also provide novel rationales for designing the next-generation cancer metabolism drugs.

Keywords: Cancer metabolism; cell signaling; drug development; metabolic plasticity.

Figure 1

Interactions and inhibitors of cellular signaling and metabolism. Glucose, glutamine, and fatty acid metabolism are regulated by various types of oncogenic, tumor suppressive signaling. Oncogenic proteins (green), including PI3K/AKT, MYC, RAS, YAP/TAZ, and HIF-1, upregulate expression of nutrient transporters and metabolic enzymes (yellow). Tumor suppressive AMPK, miR-23, SIRT4, GSK3, and p53 inhibit metabolic processes (red). Some metabolism-targeting drugs (white) inhibit key metabolic steps, including glycolysis, NAD⁺ regeneration, fatty acid synthesis, and glutaminolysis. G6PD, glucose-6-phosphate dehydrogenase; PGD, phosphogluconate dehydrogenase; GPI, glucose-6-phosphate isomerase; PFK, phosphofructokinase; DHAP, dihydroxyacetone phosphate; G3P, glyceraldehyde 3-phosphate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; PGK1, phosphoglycerate kinase 1; 3PG, 3-phosphoglycerate; PHGDH, phosphoglycerate dehydrogenase; PSAT, phosphoserine transaminase; MCT, monocarboxylate transporter 1; MPC, mitochondrial pyruvate carrier; SucCoA, Succinyl-CoA; OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; GSK3, glycogen synthase 3; HIF-1, hypoxia induced factor-1; FABP3, fatty acid binding protein 3; ADRP, adipose differentiation-related protein; SIRT4, sirtuin 4; GOT1/2, aspartate aminotransferase.

Figure 2

Cancer metabolism promotes redox homeostasis during metastasis. (a) Oncogenic signaling, such as KRAS, HIF-1, and MYC, activates NADPH-producing metabolic processes. NADPH provides reducing power for recycling antioxidant metabolites. (top) Aberrant NRF2 activation in cancer cells upregulates expression of redox metabolites and enzymes. (bottom) (b) Cancer activates various metabolic enzymes and oncogenic signaling during each step of the metastatic cascade. YAP/TEAD, NF-κB, and AKT signaling induces invasion by enhancing metalloprotease expression. Redox homeostasis-related metabolic processes are increased during circulating tumor cell (CTC) formation. NRF2, HO-1 enhances antioxidant enzymes and heme metabolism. The PPP and glutamine metabolism facilitate NADPH accumulation. During the colonization step, PGC1 increases metabolic plasticity and activates ATP-generating pathways. SOD, superoxide dismutase; NADP, nicotinamide adenine dinucleotide phosphate; GSH, glutathione; GSSG, glutathione disulfide; PRX, peroxiredoxin; TRX, thioredoxin reductase; GRM3, metabotropic glutamate receptor 3; MT1, metallothionein 1; HO-1, heme oxygenase.