Dietary and pharmacological modification of the insulin/IGF-1 system: exploiting the full repertoire against cancer

Abstract

As more and more links between cancer and metabolism are discovered, new approaches to treat cancer using these mechanisms are considered. Dietary restriction of either calories or macronutrients has shown great potential in animal studies to both reduce the incidence and growth of cancer, and to act synergistically with other treatment strategies. These studies have also shown that dietary restriction simultaneously targets many of the molecular pathways that are targeted individually by anticancer drugs. The insulin/insulin-like growth factor-1 (IGF-1) system has thereby emerged as a key regulator of cancer growth pathways. Although lowering of insulin levels with diet or drugs such as metformin and diazoxide seems generally beneficial, some practitioners also utilize strategic elevations of insulin levels in combination with chemotherapeutic drugs. This indicates a broad spectrum of possibilities for modulating the insulin/IGF-1 system in cancer treatment. With a specific focus on dietary restriction, insulin administration and the insulin-lowering drug diazoxide, such modifications of the insulin/IGF-1 system are the topic of this review. Although preclinical data are promising, we point out that insulin regulation and the metabolic response to a certain diet often differ between mice and humans. Thus, the need for collecting more human data has to be emphasized.

Figure 1

Insulin/IGF receptor binding. As tyrosine kinase receptors, the IR and the IGF receptors, consist of an extracellular ligand-binding domain and a cytosolic tyrosine kinase domain that autophosphorylates upon ligand binding and transphosphorylates several substrates that initiate downstream signaling. The IR shares ~50 and 80% homology with the ligand-binding and tyrosine kinase domain, respectively, of the IGF-1 receptor (IGF-1R). It exists in two isoforms, IR-A and IR-B, which promote either mainly mitogenic or metabolic effects, depending on the ligand and the cellular context, allowing cells flexibility in responding to mainly one or the other stimulus. In general, IR-A is preferentially associated with mitogenic and anti-apoptotic signaling, whereas IR-B is associated with cell differentiation and metabolic effects. A predominant expression of IR-A has correspondingly been found in fetal tissue and tumors with autocrine production of IGF-2, which binds this receptor with 30–40% affinity compared with insulin. In this way, these tumors promote cell proliferation in an autocrine manner.^, IGF-2 also binds to the IGF-1R, whereas IGF-1 binds to its own IGF-1R and to hybrid receptors of IGF-1R and IR-A as well as IGF-1R and IR-B.^, Physiological concentrations of insulin show no measurable binding to the IGF-1R both in vitro and in vivo. Nevertheless, in mammals, insulin may be the major controller of insulin/IGF-1 action due to its effect on the bioavailability of IGF-1.

Figure 2

Insulin/IGF-1 signaling network and its modulation by dietary restriction. Dietary restriction in the form of overall calorie restriction or specific restriction of carbohydrates or protein has specific effects on the insulin/IGF-1 system that transduces cellular signals through its insulin and IGF-1 tyrosine kinase receptors. This picture can only provide a partial overview of the complexity of this signaling network. The classical action of activated extracellular signal-regulated kinase (ERK)-1 and ERK-2 is their translocation into the nucleus where they activate mitogenic transcription factors. Similarly, mTORC1 targets transcription factors that increase proliferation and counteract apoptosis. Activation of mTORC1 via IR/IGF-1R−PI3K−AKT converges with its activation by amino acids at the lysosomal membrane. There, the guanosine triphosphatase (GTPase) Rheb (Ras homolog enriched in brain) stimulates mTOR activity, whereas a lack of growth signals activates the tumor suppressor tuberin (TSC2), which translocates to the lysosomal membrane and inhibits Rheb-stimulated mTORC1 activation. High insulin levels activate AKT that phosphorylates and inactivates TSC2, whereas CR or glucose withdrawal induce energy stress, decrease the intracellular ATP/AMP ratio and activate TSC2 through liver kinase B1 (LKB1)—adenosine monophosphate-activated protein kinase (AMPK) signaling. AMPK can also directly inhibit mTORC1 by phosphorylating the regulatory-associated protein of mTOR (Raptor). AMPK has similar actions to the class III histone deacetylase SIRT1, which is a NAD⁺-dependent enzyme that is also activated under DR-induced energy stress through an increase in the NAD⁺/NADH ratio. AMPK and SIRT1 amplify each other and both activate the peroxisome proliferator-activated receptor gamma 1α coactivator (PGC-1α) protein that cooperates with peroxisome proliferator-activated receptor α (PPARα) to induce major metabolic shifts under DR such as an upregulation of lipid oxidation and downregulation of glycolysis. mTORC1 inhibits these actions, providing another link to insulin/IGF-1 signaling.

Figure 3

Glycolytic pathways in tumor cells. Sketch of the most important glucose-degrading metabolic pathways in a tumor cell. Glucose uptake into the cytoplasm is accomplished via specific transpcorters (GLUTs) that are often overexpressed in tumor cells. Here the enzyme hexokinase (HK) phosphorylates glucose to glucose-6-phosphate (glucose-6-P). This metabolite either gets degraded to pyruvate via several intermediate steps of glycolysis or serves as the precursor for conversion into ribulose-5-phosphate in the oxidative part of the pentose phosphate pathway (PPP). In the PPP, CO₂ gets released and the reducing equivalent NADPH is produced. The generated ribulose-5-phosphate either serves as the basis for de novo synthesis of nucleotides or is converted to various C3–C7 sugars through the transketolase/transaldolase reaction in the non-oxidative part of the PPP. Pyruvate, the end product of glycolysis, usually gets transported into the mitochondria, converted to acetyl-CoA and channeled into the TCA cycle for oxidative degradation. In case of insufficient oxygenation, dysfunctional mitochondria or metabolic reprogramming through hyperactivation of AKT–mTOR signaling, pyruvate is increasingly converted to lactate via the enzyme lactate dehydrogenase (LDH). Lactate gets transported out of the cell by monocarboxylate transporters (MCTs). The PI3K–AKT pathways increases glycolytic rate by the mechanisms depicted and described in the main text. Dashed arrows indicate several intermediate steps.

Figure 4

Effects of CR on IGF-1 and IGF-1R mRNA expression and growth of the CT-2A astrocytoma. For conditions a and b, tumors were implanted into the brains of C57BL/6J mice. At 10 days post tumor implantation, mice were randomly switched to either an unrestricted (UR; n=9) or CR (n=9) diet that aimed at reducing body weight by ~30%. In condition c, tumors were implanted subcutaneously and CR started at day 14; the Kaplan–Meier survival curve indicates significantly longer survival for CR compared with UR (P=0.01). Figure parts reproduced with permission from.