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Abstract

Liver cancer is fundamentally physiologically different from the surrounding liver tissue. Despite multiple efforts to target the altered signaling pathways created by oncogenic mutations, not many have focused on targeting the altered metabolism that allows liver cancer to develop and grow. Still to be resolved is the question of whether the altered metabolic pathways in this cancer differ enough from the surrounding noncancerous cells to allow for the development of potent and specific compounds. Clinical studies of metabolic modulators would provide some more information with regard to the feasibility of this approach. Furthermore, as it appears that oncogenic signaling is essential to this cancer’s altered metabolism, it stands to reason that targeting this altered signaling may allow the exploitation of specific metabolic vulnerabilities in combination with other drugs for enhanced efficacy. The identification of biomarkers of metabolic sensitivity will also be essential to determine whether these drugs will have the desired effect.

Keywords

genomics proteomics molecular biology automated biology

Introduction

Even as cancer death rates overall are gradually falling, liver cancer incidence and mortality continue to climb.¹ Hepatocellular carcinoma (HCC), the most common primary liver cancer and the second leading cause of cancer deaths worldwide,^2,3 typically occurs in the setting of chronic liver disease and cirrhosis. It has a poor prognosis, with a 5-year survival of 16.6%.⁴ This is due to (1) its aggressive and heterogeneous biology, (2) its usual occurrence in the background of severe liver disease, and (3) the lack of effective therapeutics for advanced disease. Thus far, cures are possible only if the disease is localized and treated with resection, transplantation, and/or locoregional treatment.⁵ Those with beyond localized disease (~70% of the total) have 5-year survival rates of 10% or less.⁶

The oral multikinase inhibitor sorafenib is the only drug thus far with proven benefit in the treatment of nonresectable HCC. Although small, the survival benefit was statistically significant compared to supportive care alone, thus establishing sorafenib as the standard systemic treatment. Nevertheless, sorafenib treatment has not reduced recurrence rates after resection.⁷ There have been multiple failures of other drugs and combinations. The chemotherapy-refractory nature of hepatocellular cancer has been ascribed to the high rate of expression of drug resistance genes, such as P-glycoprotein, among others.⁸

What further complicates matters in HCC is that survival often depends also on liver function, not just tumor aggressiveness. Therefore, the true benefit of systemic chemotherapy in patients with advanced HCC can be obscured by its tolerability and how much it exacerbates hepatic dysfunction.⁹ This necessitates new approaches to treating HCC. The liver is essential to lipid, glucose, and cholesterol metabolism. The pathological conditions that affect the liver, including HCC, also affect its metabolic function. These include alterations in functions such as gluconeogenesis, fatty acid oxidation, and lipid storage and transport. Targeting these pathways may constitute a novel approach. Targeting metabolic pathways in HCC has been tried previously. Gemcitabine, a nucleoside analogue and thus a nucleic acid pathway inhibitor, has shown little activity at best¹⁰ and no activity in multiple other trials.^11,12 However, as we accrue more information and experience from ongoing studies in cancer metabolism, it is prudent to review what has been learned and to discuss different approaches to targeting HCC metabolism.

Metabolism as a Target in Treating Cancer

The cancerous state alters cellular metabolism and requires elevated metabolic function for growth and proliferation. Malignant cells need to fuel the reactions that are needed for growth and replication. These cells also need larger pools of nucleotides, proteins, lipids, and carbohydrates to supply this growth and replication. Such alterations have been recognized as potential markers of malignancy as early as 1924 by Otto Warburg, when he described an increase in aerobic glycolysis in cancer cells. They have been used clinically both for the diagnosis of malignancy via ¹⁸F-deoxyglucose positron emission tomography (¹⁸FDG-PET) and for their treatment using antiproliferative agents like 5-fluorouracil, methotrexate, and gemcitabine, all of which inhibit metabolic enzymes.^13,14 More recently, other metabolic alterations accompanying malignant transformation are beginning to be delineated. These include increased flow through the pentose phosphate pathway, lipid synthesis, and consumption of glutamine, among others.¹⁴ Thus, increasing effort is being dedicated to identifying agents targeting cancer cells based on their metabolic alterations. Targeting tumor metabolic programs (e.g. by inhibiting flow through glycolysis) can decrease adenosine triphosphate (ATP) production and reduce the availability of intermediates for the synthesis of lipids, proteins, and nucleic acids necessary for cell growth and division, thus inhibiting tumor growth.¹⁵

Normal Liver Metabolism

Before developing effective and safe therapies targeting HCC metabolism, it is important to understand the characteristics of HCC metabolism and how it is different both from other cancers and from normal liver. As the main metabolic organ of the body, the liver is central to homeostasis. It is the primary site of carbohydrate, protein, and lipid synthesis, storage, and redistribution.¹⁶

Hepatocytes absorb glucose from the blood via glucose transporter type 2 (GLUT2), a high-capacity transporter with a low affinity for glucose. Once inside, glucose is phosphorylated to glucose-6-phosphate (G6P) by glucokinase (GCK).¹⁷ GCK is under the transcriptional control of a number of factors, including sterol response binding protein 1c (SREBP-1c), hepatic nuclear factor 4 alpha (HNF4a), hepatic nuclear factor 6 (HNF6), forkhead box protein O1 (FoxO1), and upstream stimulatory factor 1 (USF1).¹⁶ Depending on the systemic metabolic state, G6P is either consumed in glycolysis or used to synthesize glycogen. In glycolysis, glucose is converted to pyruvate, gaining two ATP and two nicotinamide adenine dinucleotide (NADH) molecules. This process is regulated directly or indirectly by a number of enzymes and metabolic products, including GCK, phosphofructokinase, fructose-1,6-bisphosphate, adenosine monophosphate (AMP), and pyruvate kinase. Pyruvate kinase is activated by its substrate and inhibited by high levels of ATP. Pyruvate can be oxidatively converted to acetyl-CoA for use in the citric acid cycle or for lipogenesis. Hepatocytes can also degrade G6P via the pentose phosphate pathway (PPP). This generates the antioxidant nicotinamide adenine dinucleotide phosphate (NADPH), a substrate for the synthesis of lipids and cholesterol.

Glycogen synthase converts G6P to UDP-glucose on the pathway to glycogen. It is allosterically activated by G6P and phosphorylated and inactivated by glycogen synthase kinase 3 (GSK3). GSK3 is regulated by the Akt/phosphoinositide-3-kinase (PI3K) pathway and therefore by insulin signaling, as well as by SREBP-1c, AMP-activated protein kinase (AMPK), and protein kinase A (PKA).¹⁸

During fasting, the liver breaks down glycogen; longer fasting periods lead to gluconeogenesis. Glycogen phosphorylase, which produces glucose-1-phosphate from glycogen, is activated by AMP and PKA. Gluconeogenesis is induced by high amounts of acetyl-CoA.¹⁹ Gluconeogenesis is regulated through a complex interplay among hormones such as insulin, glucagon, glucocorticoids, and transcriptional factors such as FoxO1, peroxisome proliferator-activated receptor alpha (PPARα), PPAR gamma coactivator 1-alpha (PGC1α), HNF4a, and cAMP-response element-binding protein (CBP).²⁰

There is a large overlap, as well as interactions, between hepatic glucose and lipid metabolism. Lipids can be absorbed from the diet, synthesized in hepatic lipogenesis, or released from lysosomes by autophagy. Depending on the systemic metabolic state, they can be metabolized or converted to triacylglycerols for storage. During fasting, fatty acid oxidation (also known as beta oxidation) provides the bulk of energy. Hepatic lipogenesis (i.e. the synthesis of fatty acids using acetyl- or malonyl-CoA) is catalyzed by acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). This process is highly regulated by a complex interaction among a number of nuclear receptors, including PPARs.²¹ NADPH, synthesized in the PPP, is required as a reducing reagent in fatty acid elongation.

The overlap between glucose and lipid metabolism can be seen in the fact that nuclear receptors mediate insulin signaling. FAS expression is also increased by the action of insulin through the PI3K pathway.²² Furthermore, the carbohydrate-responsive element binding protein (ChREBP) binds and activates motifs in the promoter regions of triglyceride synthesis genes, in response to glucose and synergistically with SREBP-1c to induce expression of FAS and ACC.²³

Macroautophagy is also important in maintaining hepatic lipid homeostasis.²⁴ Through this pathway, organelles and unused proteins are marked for degradation and conversion into sources of energy sources in fasting, especially in liver lipolysis.^25,26 This process releases fatty acids, which can then be catabolized in the tricarboxylic acid (TCA) cycle (also known as the Krebs cycle). Long fasting states can repress mechanistic target of rapamycin (mTOR), thus releasing its inhibition of autophagy. On the other hand, insulin and the activation of its receptor induce lipogenesis and inhibit lipolysis.

Fatty acid oxidation in the endoplasmic reticulum (ER), peroxisomes, and mitochondria converts fatty acids to acetyl-CoA. This allows for efficient storage and later for the rapid generation of energy. Fatty acyl-CoAs are formed by acyl-CoA-synthetase, allowing short- and medium-chain fatty acids to cross lipid membranes. Long-chain fatty acids need to be actively transported across membranes by carnitine palmitoyltransferase 1 (CPT1). Insulin receptor activation leads to lipogenesis, which leads to the accumulation of intermediates such as malonyl-CoA. Malonyl-CoA inhibits CPT1,²⁷ thus blocking fatty acid oxidation and promoting lipogenesis and storage of lipids.²⁸ In fatty acid oxidation, electrons drive ATP synthesis. Acetyl-CoA can also go through the TCA cycle or used to generate ketone bodies.²⁹ This process is again controlled by PPARα and insulin signaling through transcriptional regulation of HMG-CoA synthase.

Liver Cancer Metabolism

HCC is metabolically different from normal liver tissue in many ways, including glycolysis, the citric acid cycle, the PPP, and amino acid metabolism. In general, these include more glycolysis and lactate production, as well as a higher lactate-to-pyruvate ratio in HCC.³⁰ Normally, glucose undergoes glycolysis and is converted to pyruvate, which then goes through the TCA cycle in the mitochondria to generate ATP through oxidative phosphorylation. But cancer cells have increased glycolysis and fermentation to lactate even though this is a less efficient source of ATP. This shift, known as the Warburg effect, is thought to be due to the fact that glucose provides most of the carbon needed for the production of energy and the biosynthesis of macromolecules. This metabolic reprogramming, associated with much higher glucose consumption, is required for the anabolic state needed to provide the basic materials for rapid cell growth and division. This shift away from catabolism is correlated with and likely caused by changes in signal transduction and mutations in oncogenic drivers and tumor suppressors.^31,32

HCC in general is thought to have highly upregulated glycolytic activity, along with increased hexokinase 2 (HK2) activity and GLUT1 expression. This leads to alterations in glucose utilization, possibly providing therapeutic and diagnostic modalities.³³

Another key determinant of the Warburg effect is pyruvate kinase M2 (PKM2), an isoform of the enzyme that catalyzes the final step of glycolysis, the synthesis of pyruvate and ATP from phosphoenolpyruvate and ADP. This isoform is closely linked to embryogenesis, tissue regeneration, and carcinogenesis.^34,35 PKM2 favors the Warburg effect by having low enzymatic activity. Its activation has been associated with tumor growth and poor outcomes,^36,37 although its effects are likely pleotropic.³⁸ Recent studies hint at a possible therapeutic or sensitizing effect for PKM2 inhibition through the PARP14-JNK1-PKM2 regulatory axis in HCC.³⁹

Other recent work shows that lipid and glucose metabolism also plays a significant role in hepatic carcinogenesis.⁴⁰ Not only has the increase in fatty liver disease been associated with HCC,⁴¹ but the metabolic syndrome itself appears to increase the risk of HCC.⁴² There is increasing evidence for the importance of lipids and lipid metabolism in hepatocarcinogenesis, as HCC can arise in fatty liver disease without cirrhosis.⁴³

Members of the insulin receptor pathway, such as PI3K/Akt, demonstrate higher activity in cancerous tissue compared with the surrounding tissue in HCC. GSK3b and mTOR have also been implicated.⁴⁴ These proteins also interact with beta-catenin, autophagy, and glycogen synthesis. Tumor necrosis factor (TNF), interleukin (IL)–6, and in turn JAK/STAT and ERK also appear to mediate HCC development.⁴⁵

PPARs too are important players in hepatocarcinogenesis by regulating fatty acid oxidation and transport. They also act on the Akt pathway through tribbles homolog 3 (TRIB3).⁴⁶ PPARα activity leads to hepatocarcinogenesis in some models,⁴⁷ possibly acting through STAT3,⁴⁸ whereas PPARγ seems to have the opposite effect by improving fatty liver disease and also by inhibiting HCC tumor growth.^49,50 All of these studies, however, must be understood in view of the fact that much of these data come from tissue culture and mouse models, with limited correlation with human HCC.

Other pathways also figure into the changes in metabolic programming. For example, in addition to glucose, the TCA cycle uses other carbon sources, including some amino acids, into precursors for other biomolecules. For example, glutamine is an important carbon source in many cancers.⁵¹ Therefore, it is likely that alterations in amino acid metabolism also play important parts in HCC metabolism. It is likely that the source of the carbon varies among tumors and possibly may even depend on the specific microenvironment.

Targeting Pathways in HCC

Pathway targeting in HCC has thus far mostly been limited to inhibiting angiogenesis. While several lines of investigation target epidermal growth factor receptor and vascular endothelial growth factor receptor (EGFR and VEGFR, respectively), these are at best still quite exploratory.^52,53 Lenvatinib, a VEGFR blocker with potent antiangiogenic effects, has shown promising results in phase I/II clinical trials in HCC. The phase III REFLECT trial comparing it to sorafenib has completed patient recruitment, but the results are not yet available.⁵⁴ Regorafenib, another VEGFR inhibitor, has also shown promise in treating patients with HCC progressing on sorafenib, despite reports on its hepatotoxicity.⁵⁵ Cabozantinib, a dual inhibitor of MET (also known as hepatocyte growth factor receptor [HGFR]) and VEGFR, blocks the hepatocyte growth factor (HGF)–stimulated MET pathway and has significant antitumor activity in HCC cells.⁵⁶ MET inhibitor tivantinib has had some promising results in patients with HCC with high MET expression.⁵⁷ A phase III trial is currently under way (clinicaltrials.gov identifier: NCT02029157).

The Raf/MEK/ERK pathway has also been implicated in HCC tumorigenesis.^58,59 Raf (receptor activation factor) kinase regulates the mitogen-activated protein (MAP) kinase signaling pathway, a key to cellular functions such as growth, transformation, and apoptosis. MEK1 overexpression in HCC cell lines has been shown to enhance tumor growth and survival by preventing apoptosis.⁶⁰ This suggests a potential therapeutic role for Raf kinase and MEK inhibitors, such as refametinib.⁶¹ Other approaches have included inhibitors of hepatocyte growth factor/c-Met⁶² and mTOR inhibitors, such as everolimus.^63,64 A phase III randomized trial of tivantinib is ongoing, but everolimus appeared to yield no survival benefit.⁶⁵

Metabolism, however, provides an orthogonal approach to the treatment of HCC. The alterations in cancer metabolism may provide targets for the development of novel compounds aimed at a fundamental characteristic of cancer biology.

Aerobic Glycolysis

Aberrant signaling in HCC can result in the induction of glycolysis, meaning that the tumors’ reliance on large amounts of glucose to generate ATP, biosynthetic intermediates, and reducing equivalents may provide a therapeutic target. Several proteins that regulate glycolysis have been tested as potential therapeutic targets.¹⁵ In HCC, glucose transporters such as GLUT1³³ and specific isoforms of hexokinase are overexpressed,⁶⁶ making them potential targets.⁶⁷ Hexokinase 2, not normally expressed in most noncancerous tissues, has been targeted in multiple studies by resveratrol,⁶⁸ microRNAs (miRNAs),^66,69 and Ras related glycolysis inhibitor and calcium channel regulator (RRAD),⁷⁰ among others. There has been renewed interest in small molecules that inhibit hexokinases, such as 2-deoxy-D-glucose. The toxicity of these drugs has been mitigated mostly by using them in comparatively small doses and in combination with other drugs such as sorafenib.⁷¹ Ongoing investigations in the development of small molecules with improved specificity toward hexokinase isoforms overexpressed in HCC are under way.

Another glycolytic enzyme that has been targeted is the pyruvate dehydrogenase (PDH) complex. This mitochondrial complex converts pyruvate to acetyl-CoA and regulates the flow of pyruvate into the mitochondria for oxidative phosphorylation versus conversion to lactate in the cytosol. Because it appears that isoforms of PDH kinase (PDHK) are overexpressed in certain cancers, the inhibition of PDHK by miRNA, RNA interference (RNAi), and small-molecule inhibitors such as dichloroacetate (DCA), has been shown to be efficacious in several in vitro and in vivo models.^72–75 Although only somewhat efficacious on its own, it may prove to be an effective means of increasing tumor sensitivity to chemotherapy.

Inhibition of PDHK using DCA can activate PDH and lead to increased oxidative phosphorylation and presumably decreased aerobic glycolysis. DCA has been shown to enhance the sensitivity of HCC to other chemotherapeutic agents such as adriamycin and sorafenib.^74,75 However, DCA itself can have significant adverse effects, while lacking adequate efficacy on its own.⁷⁶

Lactate dehydrogenase (LDH), too, is a key regulator of the flow of pyruvate by converting cytoplasmic pyruvate to lactate. The variable expression of its two isoforms, specifically the increased levels of LDH in cancer cells, has been implicated in increasing aerobic glycolysis, as well as being an important prognostic indicator for HCC outcomes.^77–79 Much evidence points to the fact that the inhibition of LDH can slow tumor growth.⁸⁰ Although early stage clinical trials have had mixed results, other more specific inhibitors are being developed.^81,82

Other Sugar Metabolism/Oxidative Phosphorylation

Mutations that correlate with the prognosis of HCC patients have been found in several citric acid cycle enzymes, including succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH).^83,84 Interestingly IDH mutations lead to the production of a new metabolite, (R)-2-hydroxyglutarate (2HG), which can transform cells in vitro, possibly by inhibiting demethylases, leading to hypermethylated DNA and retention of a stem cell–like character.^85–87 Clinical studies are under way examining the effect that targeting the TCA cycle with specific small molecules may have on tumors.⁸⁸

Amino Acid Metabolism

High expression of amino acid transporters SLC38A1 and SLC7A5 (solute carrier family members 38A1 and 7A5, respectively) is significantly associated with shorter survival in HCC patients. It also appears that inhibition of these transporters and mTORC1 blocks YAP1/TAZ-mediated tumorigenesis in the liver.⁸⁹ There also appears to be strong HCC risk associations for circulating levels of some aromatic, branched-chain, and glucogenic amino acids and biogenic amines.⁹⁰

Targeting Glutamine

Even though glutamine is a nonessential amino acid that can be synthesized from glucose, some cancer cell lines exhibit high rates of glutamine uptake, often associated with increased Myc or KRAS signaling.^91,92 This appears to be due at least in part to glutamine’s roles in taking up essential amino acids, sustaining activation of mTOR, maintaining the mitochondrial membrane potential and integrity, and supporting the production of the NADPH needed for redox control and the synthesis of macromolecules.^51,93

Glutamine transporters, including SLC1A5 (ASCT2) and large neutral amino acid transporter 1 (LAT1), can be upregulated in malignancies.⁹⁴ Glutaminase isoenzymes, which convert glutamine to glutamate, are critical in the response to metabolic and oxidative stress and have different expression levels than in normal cells.⁹⁵ Targeting glutamine uptake into cancer cells by inhibiting LAT1 using 2-amino-(2,2,1)-heptane-2-carboxylic acid (BCH) inhibits tumor proliferation and growth.^96,97 Similarly, inhibiting ASCT2 by L-γ-glutamyl-p-nitroanilide (GPNA) leads to the blockade of mTOR signaling and induction of autophagy in cancer cells. In another study, ASCT2 inhibition reduced growth in a number of lung cancer cell subtypes, effects likely mediated through the inhibition of mTOR pathway activity.⁹⁸ Inhibitors of glutaminases, such as bis-2-(5-phenylacetamido-1,2,4-thiodiazol-2-yl)ethyl sulfide (BPTES), have been shown to slow tumor growth and increase cancer cell death.^99–101

The nuclear receptor liver receptor homolog 1 (LRH-1) also has been implicated in coordinating glutamine-induced metabolism and hepatocarcinogenesis. LRH-1 appears to modulate the expression and activity of mitochondrial glutaminase 2 (GLS2). Deletion of LRH-1 reduces glutamine deamination, reduces glutaminolysis, and inhibits mTORC1 signaling, ultimately inhibiting proliferation.¹⁰²

In conclusion, one big challenge in targeting metabolic pathways as a clinical strategy is the difficulty in achieving a therapeutic window and selecting cancer metabolism without targeting other normal but rapidly proliferating cells such as immune cells. Another challenge is that tumor cells exhibit metabolic flexibility, whereby they can shift fuel sources when supplies become limited.¹⁰³ Combination therapy could be used to overcome these challenges, whether by inhibiting multiple metabolic pathways at once or by sensitizing tumors to chemotherapeutic drugs.¹⁰⁴ Overall, using the metabolic differences between liver cancer and the nontumor liver holds great promise for the development of therapeutic and diagnostic tools for this difficult disease.

Footnotes

Declaration of Conflicting Interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

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Metabolic Pathway Inhibition in Liver Cancer

Abstract

Keywords

Introduction

Metabolism as a Target in Treating Cancer

Normal Liver Metabolism

Liver Cancer Metabolism

Targeting Pathways in HCC

Aerobic Glycolysis

Other Sugar Metabolism/Oxidative Phosphorylation

Amino Acid Metabolism

Targeting Glutamine

Footnotes

Declaration of Conflicting Interests

Funding

References