Targeting Notch signaling for cancer therapeutic intervention

The Notch signaling pathway is an evolutionarily conserved, intercellular signaling cascade. The Notch proteins are single-pass receptors that are activated upon interaction with the Delta (or Delta-like) and Jagged/Serrate families of membrane-bound ligands. Association of ligand-receptor leads to proteolytic cleavages that liberate the Notch intracellular domain (NICD) from the plasma membrane. The NICD translocates to the nucleus, where it forms a complex with the DNA-binding protein CSL, displacing a histone deacetylase (HDAc)-corepressor (CoR) complex from CSL. Components of a transcriptional complex, such as MAML1 and histone acetyltransferases (HATs), are recruited to the NICD-CSL complex, leading to the transcriptional activation of Notch target genes. The Notch signaling pathway plays a critical role in cell fate decision, tissue patterning, morphogenesis, and is hence regarded as a developmental pathway. However, if this pathway goes awry, it contributes to cellular transformation and tumorigenesis. There is mounting evidence that this pathway is dysregulated in a variety of malignancies, and can behave as either an oncogene or a tumor suppressor depending upon cell context. This chapter highlights the current evidence for aberration of the Notch signaling pathway in a wide range of tumors from hematological cancers, such as leukemia and lymphoma, through to lung, skin, breast, pancreas, colon, prostate, ovarian, brain, and liver tumors. It proposes that the Notch signaling pathway may represent novel target for cancer therapeutic intervention.