Notch signaling, hypoxia, and cancer

Abstract

Notch signaling is involved in cell fate determination and deregulated in human solid tumors. Hypoxia is an important feature in many solid tumors, which activates hypoxia-induced factors (HIFs) and their downstream targets to promote tumorigenesis and cancer development. Recently, HIFs have been shown to trigger the Notch signaling pathway in a variety of organisms and tissues. In this review, we focus on the pro- and anti-tumorigenic functions of Notch signaling and discuss the crosstalk between Notch signaling and cellular hypoxic response in cancer pathogenesis, including epithelia-mesenchymal transition, angiogenesis, and the maintenance of cancer stem cells. The pharmacological strategies targeting Notch signaling and hypoxia in cancer are also discussed in this review.

Keywords: Notch signaling; cancer; hypoxia; hypoxia-induced factors pathway; therapeutics.

Figure 1

Overview of the Notch signaling pathway. The Notch receptor is produced in the endoplasmic reticulum (ER) and undergoes S1-cleavage in the Golgi compartment. The cleavage results in the formation of a heterodimer receptor, consisting of a Notch extracellular domain (NECD) and a Notch transmembrane and intracellular domain (TMIC), which is then transported to the plasma membrane. Upon interacting with a transmembrane ligand, the Notch receptor undergoes two sequentially cleavage, releases the Notch intracellular domain (NICD), which translocates into the nucleus. In the cell nucleus, NICD forms a ternary complex with the DNA-binding protein CSL and MAML to regulate transcription of downstream genes. A detailed description of the various domains in Notch receptor is presented in the box on the top. Notch receptor consists of a NECD, a transmembrane domain (TMD), and a NICD. NECD consists of epidermal growth factor (EGF) - like repeats domain, and a negative regulatory region (NRR), which including three Lin Notch repeats (LNR) and a heterodimerization (HD) domain. EGF-like repeats 11 and 12 function as specific protein binding domains mediating interaction with ligands. NICD consists of a RBPJ associated molecule (RAM), ankyrin repeats (ANK), a translational active domain (TAD), and a PEST domain.

Figure 2

A Crosstalk between Notch signaling and hypoxia pathway. Upon activation of the Notch receptor, the Notch intracellular domain (NICD) accumulates in the cell nucleus and activates target genes. Hypoxia induces the canonical hypoxia response pathway, which involves the activation of hypoxia response element (HRE)-driven target genes. Under hypoxic conditions, hypoxia-induced factors-1α (HIF-1α) potentiates Notch-dependent activation of target genes through interaction with the NICD. Besides, HIF-1α interacts with γ-secretase and upregulated γ-secretase activity. Factor-inhibiting HIF-1 (FIH-1) hydroxylates the asparagine residues of HIF-α and NICD, leading to inactivation of Notch and hypoxia signaling pathways. Hypoxia decreases the activity of FIH-1. In addition, FIH-1 binds NICD more efficiently than HIF-1α. NICD sequesters FIH-1 away from HIF-1α, indirectly resulting in an activation of HRE-driven target genes.

Figure 3

The potential therapeutics targeting Notch signaling pathway. Here are several strategies to modulate Notch signaling pathway: (I) inhibitors of Notch pre-processing, (II) receptor and ligand antibodies blocking ligand-receptor interaction, (III) inhibitors of the trimeric transcriptional complex assembly, (IV) molecules activating Notch signaling. ER, endoplasmic reticulum; NICD, Notch intracellular domain; NRR, negative regulatory region; NMHC, N-methylhemeanthidine chloride; MAML, Mastermind like transcriptional coactivator; GSIs, γ-secretase inhibitors.