Figure - available from: Frontiers in Pharmacology
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Notch receptors are initially produced as a solitary polypeptide in signal-receiving cells. These receptors are subsequently divided by Furin-like convertase(s) in the trans-Golgi network (S1) and combine to create a heterodimer. During trafficking, this heterodimeric receptor is conveyed to the cellular membrane. In the meantime, Notch ligands in sender cells can attach to Notch receptors in receiver cells. The contact between the receptor and ligand triggers a second cleavage (S2) in the extracellular domain, which is facilitated by the ADAM (A disintegrin and metalloprotease). The Notch extracellular domain (NECD) has a role in the binding of the ligand. Subsequently, a third cleavage (S3) takes place within the transmembrane domain, facilitated by the gamma-secretase function of the presenilin, Nicastrin, Anterior pharynx-defective 1 (APH-1), and Presenilin enhancer 2 (PEN-2) multi-protein complex. Lastly, the intracellular domain of Notch (NICD) is liberated and migrates to the nucleus, where it interacts with the transcription factor CSL (CBF1, Suppressor of Hairless, Lag-1). This connection results in the stimulation of transcription by blocking co-repressors and simultaneously attracting co-activators like mastermind, so facilitating the transcription of Notch target genes. Note: Mastermind-like (MAML); Histone acetyl transferases (HATs); Ski-interacting protein (SKIP); MYC proto-oncogene (Myc); Cold-inducible RNA-binding protein (CIR); Histone deacetylases (HDAC); Nuclear receptor corepressor 2 (SMRT); C-terminal binding protein (CtBP).
Source publication
Notch signaling pathway is activated abnormally in solid and hematological tumors, which perform essential functions in cell differentiation, survival, proliferation, and angiogenesis. The activation of Notch signaling and communication among Notch and other oncogenic pathways heighten malignancy aggressiveness. Thus, targeting Notch signaling offe...
Citations
... The Notch signaling pathways are divided into canonical and non-canonical pathways. The canonical pathway plays a significant role in cell fate determination and intercellular communication, regulating embryonic development, tissue differentiation, and gene regulation, as well as contributing to both benign and malignant diseases [34]. The Notch signaling pathway involves multiple steps for the maturation and activation of Notch proteins [35] (Figure 2). ...
Notch signaling is an evolutionarily conserved, multifunctional pathway involved in cell fate determination and immune modulation and contributes to the pathogenesis of autoinflammatory diseases. Emerging evidence reveals a bidirectional interaction between Notch and the gut microbiota (GM), whereby GM composition is capable of modulating Notch signaling through the binding of microbial elements to Notch receptors, leading to immune modulation. Furthermore, Notch regulates the GM by promoting SCFA-producing bacteria while suppressing proinflammatory strains. Beneficial microbes, such as Lactobacillus and Akkermansia muciniphila, modulate Notch and reduce proinflammatory cytokine production (such as IL-6 and TNF-α). The interaction between GM and Notch can either amplify or attenuate inflammatory pathways in inflammatory bowel diseases (IBDs), Behçet’s disease, and PAPA syndrome. Together, these findings provide novel therapeutic perspectives for autoinflammatory diseases by targeting the GM via probiotics or inhibiting Notch signaling. This review focuses on Notch–GM crosstalk and how GM-based and/or Notch-targeted approaches may modulate immune responses and promote better clinical outcomes.
... Genistein suppresses the expression of critical molecules like cyclin B1, Bcl-2, and Bcl-XL, which are essential for cancer cell proliferation and resistance to apoptosis. Cyclin B1 regulates cell cycle progression, and its reduction halts cell division, while Bcl-2 and Bcl-XL are anti-apoptotic proteins whose downregulation shifts the balance toward apoptosis, eliminating TNBC cells (Yang et al. 2024). ...
Breast cancer remains one of the leading causes of cancer-related deaths among women worldwide. Genistein (Gen), a phytoestrogen soy isoflavone, has emerged as a promising agent in the prevention and treatment of breast cancer due to its ability to function as a natural selective estrogen receptor modulator (SERM). This review explores the multifaceted mechanisms through which Gen and its derivatives exert their anticancer effects, including modulation of the PI3K/Akt signaling pathway, regulation of apoptosis, inhibition of angiogenesis, and impacts on DNA methylation and enzyme functions. We discuss the dual roles of Gen in both enhancing and inhibiting estrogen receptor (ER)-dependent pathways., highlighting its complex interactions with ERα and ERβ. Furthermore, the review examines the synergistic effect of combining Gen with conventional chemotherapeutic agents such as doxorubicin, cisplatin, and selenium, as well as other natural compounds like lycopene. Clinical studies suggest that while isoflavones may not significantly influence breast cancer progression in general, the high consumption of soy isoflavones is associated with reduced recurrence rates in breast cancer survivors. Importantly, Gen’s ability to modulate key signaling pathways and enhance the efficacy of existing treatments improves its potential as a valuable adjunct in breast cancer therapy. In conclusion, Gen and its derivatives offer a novel and promising approach for treatment of breast cancer. Continued research into their mechanisms of action and clinical applications will be essential in optimizing their therapeutic potential and translating these findings into effective clinical interventions.
