Modulation of Notch Signaling Pathway by Bioactive Dietary Agents

Abstract

Notch signaling is often aberrantly activated in solid and hematological cancers and regulates cell fate decisions and the maintenance of cancer stem cells. In addition, increased expression of Notch pathway components is clinically associated with poorer prognosis in several types of cancer. Targeting Notch may have chemopreventive and anti-cancer effects, leading to reduced disease incidence and improved survival. While therapeutic agents are currently in development to achieve this goal, several researchers have turned their attention to dietary and natural agents for targeting Notch signaling. Given their natural abundance from food sources, the use of diet-derived agents to target Notch signaling offers the potential advantage of low toxicity to normal tissue. In this review, we discuss several dietary agents including curcumin, EGCG, resveratrol, and isothiocyanates, which modulate Notch pathway components in a context-dependent manner. Dietary agents modulate Notch signaling in several types of cancer and concurrently decrease in vitro cell viability and in vivo tumor growth, suggesting a potential role for their clinical use to target Notch pathway components, either alone or in combination with current therapeutic agents.

Keywords: Notch signaling; cancer stem cells; chemoprevention; dietary agents.

Figure 1

Effect of dietary agents on Notch signaling pathway in cancer cells. Notch ligands, including Jagged-1, bind to, and permit cleavage of, the Notch receptor. The Notch extracellular domain is first cleaved by ADAM-10; Notch intracellular domain (NICD) is then cleaved by the gamma secretase complex. NICD translocates and activates transcription in the nucleus. Dietary agents that modulate Notch in cancer cells in vitro are listed. EGCG, epigallocatechin-3-gallate; DATS, diallyl trisulfide; RBP-Jκ, recombinant signal binding protein for immunoglobulin kappa J region; MAML, mastermind-like protein.