Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies

Abstract

Cancer cells are well documented to rewire their metabolism and energy production networks to support and enable rapid proliferation, continuous growth, survival in harsh conditions, invasion, metastasis, and resistance to cancer treatments. Since Dr. Otto Warburg's discovery about altered cancer cell metabolism in 1930, thousands of studies have shed light on various aspects of cancer metabolism with a common goal to find new ways for effectively eliminating tumor cells by targeting their energy metabolism. This review highlights the importance of the main features of cancer metabolism, summarizes recent remarkable advances in this field, and points out the potentials to translate these scientific findings into life-saving diagnosis and therapies to help cancer patients.

Keywords: Cell cycle; energy metabolism; glutaminolysis; glycolysis; mitochondria biogenesis.

Figure 1

The impacts of tumor suppressors and oncogenes on cancer metabolic reprogramming, an important cancer hallmark. Cancer metabolic alterations are the results of oncogene activation and mutant metabolic enzymes. Cancer metabolic reprogramming promotes tumorigenesis by facilitating and enabling rapid proliferation, survival, invasion, metastasis, resistance to therapies and other central cellular processes of tumorigenesis. On the other hand, as tumorigenesis advances, cancer cells acquire more mutations and changes that further enhance metabolic reprogramming and, in turn, accelerate tumor growth, proliferation and progression. Tumor suppressors, for instance, p53, and AMPK, exert their suppressive regulation on cancer metabolic alterations by blocking the function, activation and expression of essential cancer metabolic genes. Our recent results also show that 14-3-3σ, a downstream target gene of p53, effectively opposes and reverses cancer metabolic reprogramming. Our data indicate that 14-3-3σ accelerates the degradation of c-Myc, an important transcription factor promoting cancer metabolic reprogramming. In contrast, oncogenes such as c-Myc, HIF-1α, Ras, and Akt are major inducers of tumor bioenergetics alterations by upregulating the expression or activation of key metabolic enzymes such as HK2, GLS1, LDHA, among others. The balance between tumor suppressors and oncogenes has a decisive impact on the status of cancer metabolism.

Figure 2

Summary of key changes in cancer metabolic reprogramming. Cancer metabolic reprogramming is characterized by enhanced glycolysis, PPP, lipid metabolism, glutaminolysis, mitochondrial biogenesis, among others. These pathways provide cancer cells with not only essential energy but also important precursors to support large-scale biosynthesis, rapid proliferation, continuous growth, tissue invasion, metastasis, survival and resistance to anti-cancer therapies. For instance, glycolysis generates 2 ATP per glucose consumed and provides materials for PPP and other biosynthetic programs. Similarly, PPP supplies tumors with ribose-5-phosphate and NADPH. Ribose-5-phosphate is a major element for nucleotide synthesis, which is used in DNA replication, RNA synthesis, and DNA damage repair, among others. NADPH is a key line of defense counteracting oxidative stress and a crucial metabolite for a number of biosynthesis reactions. NADPH is produced by 4 biochemical reactions mediated by G6PD, 6PLGD, ME1 and IDH1. In addition, fatty acid synthesis is indispensable for formation of new cellular membranes and proliferation. A number of fatty acid synthesis enzymes such as ACC, ACLY and FASN are upregulated or activated by oncogenes such as c-Myc, HIF-1α, Akt, among others. On the other hand, FAO is also important for cancer cells because it generates energy, NADPH and other necessary metabolites. Fatty acids are imported into mitochondria by CPT1 and oxidized to generate acetyl-CoA. Acetyl-CoA fuels the TCA cycle to generate NADH and FADH₂. The latter metabolites donate electrons to mitochondrial ETC for ATP generation. CPT1 also antagonizes Bax and Bad-mediated apoptosis by preventing the formation of mitochondrial membrane transition pores and reducing cytochrome c release. Citrate produced by the TCA cycle can be transported from mitochondria to cytosol. Cytosolic citrate is used in a number of reactions to produce acetyl-CoA, oxaloacetate and isocitrate. These metabolites are important for lipid synthesis, NAPDH production, and many other central cellular processes. Mitochondrial biogenesis is also a striking feature of cancer metabolic reprogramming. Mitochondria are not only the energy generators but also the factories for synthesizing many essential metabolites for cancer growth, proliferation and metastasis. In addition, the metabolic lactate-based symbiosis is another remarkable characteristic of cancer metabolism. Cancer cells frequently upregulate LDHA to facilitate the conversion of pyruvate to lactate. Lactate is then secreted to tumor microenvironment via MCT4 transporters and can be taken by neighboring cancer cell thanks to MCT1 importers. Lactate is thereafter used for other metabolic pathways in tumors. This metabolic symbiosis facilitates the survival of cancer cells in harsh conditions. Thus, metabolic reprogramming is a major cancer hallmark. It is characterized by the upregulation of a number of inter-connected metabolic pathways providing cancer cells with vital energy and metabolites. This metabolic plasticity is essentially important because it allows cancer cells to effectively and rapidly adapt to the rapidly changing conditions of tumor microenvironment. In addition, the flexibility of cancer bioenergetics also enables rapid proliferation, continuous growth, invasion, metastasis and resistance to anti-cancer therapies. Therefore, further knowledge about cancer metabolic reprogramming is very important for successful development of precise and efficacious anti-cancer metabolism therapies. Dashed arrows indicate indirect effects or multi-step processes. Abbreviations: HK2, hexokinase 2; LDHA, lactate dehydrogenase A; G6PD, glucose-6-phosphate dehydrogenase; 6PGLD, 6-phosphogluconate dehydrogenase; ACC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; FASN: fatty acid synthase, SCD, stearoyl-CoA desaturase; CPT, carnitine palmitoyltransferase; CPT1C, carnitine palmitoyltransferase 1C; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; UCP, uncoupling proteins; MCT, monocarboxylic acid transporter; ME1, malic enzyme; IDH1, isocitrate dehydrogenase1; GLS1, glutaminase; GLUD, glutamate dehydrogenase; FAO, fatty acid oxidation; ETC, electron transport chain; PPP, pentose phosphate pathway; TCA, tricarboxylic acid cycle; α-KG, alpha-ketoglutarate.

Figure 3

Summary of the mechanism of several important drug candidates for anti-cancer metabolism therapies. Phloretin inhibits the import of glucose, a major source of nutrient for cancer cells. 2DG, 3BrPA, and Lonidamine inhibit HK2, a rate-limiting step of glycolytic pathway. 3PO blocks PFK1 activation by inhibiting PFKFB3 (PFK2). FX11 selectively inhibits LDHA, a major metabolic enzyme of cancer. BPTES and 968 suppress the function of GLS1. GLS1 is a glutaminolytic enzyme that is highly and selectively upregulated in cancer. DCA inactivates PDH kinase (PDK), thereby increasing PDH activity and enhances the conversion of pyruvate to acetyl-CoA and decreases cancer glycolysis. Metformin blocks energy production of cancer cells by inhibiting mitochondrial complex I, suppresses lipid and protein synthesis, modulates glycolysis. At the organism level, by lowering blood glucose concentration, metformin decreases glucose supply, as well as insulin and insulin-like growth factor signaling availability for tumor cells. MCT inhibitors impair the metabolic lactate-based symbiosis of cancer cells. Many other anti-cancer metabolism compounds are under development. Targeting cancer metabolism is a very promising direction for anti-cancer therapies. It is expected that inhibitors of tumor metabolism will play an important role in clinical oncology within five or ten years. These medications could be used alone or in combination with other current anti-cancer therapies to increase efficacy. Abbreviations: 2DG, 2-deoxyglucose; 3BrPA, 3-bromopyruvate; HK2, hexokinase 2; PFK1, phosphofructose kinase 1; LDHA, lactate dehydrogenase A; GLS1, glutaminase 1; DCA, dicholoroacetate; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; MCT, monocarboxylic acid transporter.