The link between the metabolic syndrome and cancer

Abstract

Since the incidence of the metabolic syndrome is on the rise in the western world, its coherence to cancer is becoming more apparent. In this review we discuss the different potential factors involved in the increase of cancer in the metabolic syndrome including obesity, dyslipidemia and Type 2 Diabetes Mellitus (T2DM) as well as inflammation and hypoxia. We especially focus on the insulin and IGF systems with their intracellular signaling cascades mediated by different receptor subtypes, and suggest that they may play major roles in this process. Understanding the mechanisms involved will be helpful in developing potential therapeutics.

Keywords: cancer; metabolic syndrome.

Figure 1

The insulin receptor (IR) with its two subtypes IR-A and IR-B, the insulin growth factor 1 receptor (IGF-IR) and the hybrid receptors (IGF-1R/IR-A and IGF-1R/IR-B). Structurally, IR and the IGF-1R have two extracellular α-subunits and two transmembrane β-subunits that are jointed to each other by disulfide bonds. Affinity, insulin binds with high affinity to IR-A or IR-B but has low affinity for IGF-1R, while insulin has no binding to the hybrid receptors. IGF-1 binds to the IGF-1R and to the hybrid receptor IGF-1R/IR-A or IGF-1R/IR-B. IGF-2 binds to IR-A, IGF-1R or to IGF-1R/IR-A hybrid receptor. Signaling, ligand binding to insulin receptor-A or to IGF-1 receptor mediates the mitogenic signaling pathway, while ligand binding to insulin receptor-B activates metabolic signaling. Binding to the hybrid receptors, leading to mitogenic or metabolic signaling, is determined by the IR isoform that formed the hybrid receptors. Reproduced by permission of the RMMJ .

Figure 2

Insulin-like growth factor 1 receptor (IGF-1R) signaling pathway. ( "->" : activation, "-●": inhibition). Binding of IGF-1 or IGF-2 or insulin to the IGF-1R α-subunit leads to autophosphorylation of β-subunit residues, which then act as docking site to insulin receptor substrates (IRS-1 to 4). Bound IRS-1 results in PI3K activation, which in turn activates Akt. The tumor suppressor phosphates and tensin homolog deleted on chromosome 10 (PTEN) inhibits PI3K. Activated Akt has many substrates; in one pathway Akt inhibits apoptosis by inactivating BCL-2 antagonist of cell death (BAD), and in the second pathway Akt regulates protein synthesis by phosphorylating tuberous sclerosis complex (TSC1/2). This phosphorylation removes the inhibition of TSC from mammalian target of rapamycin (mTOR). mTOR activates the ribosomal S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP-1), leading to protein synthesis. In energy depletion expression of the suppressor gene LKB1 and AMP raise. AMPK is activated by both mechanisms. AMPK inhibits protein synthesis through direct inhibition of mTOR or indirectly by activating the TSC complex. Hypoxia induces REDD1.The detailed interaction between REDD1 and TSC is not clear yet. We conclude that the inhibition of HIF-α by TSC might be independent of REDD1. The mitogen-activated protein kinase (MAPK) pathway can also be activated by IGF-1R activation. In this pathway IGF-1R activates the adaptor proteins, Shc and Grb2, leading to activation of Ras, Raf, MEK1/2, and ERK1/2, which results in cell proliferation.