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Updated: Mar 14, 2026
Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
Notch signalling pathway as an oncogenic factor involved in cancer development
Marlena Brzozowa-Zasada1, Adam Piecuch1, Anna Dittfeld1
1Department of Histology and Embryology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland.
Abstract:
Notch signalling is an evolutionarily conserved signalling pathway, which plays a significant role in a wide array of cellular processes including proliferation, differentiation, and apoptosis. Nevertheless, it must be noted that Notch is a binary cell fate determinant, and its overexpression has been described as oncogenic in a broad range of human malignancies. This finding led to interest in therapeutically targeting this pathway especially by the use of GSIs, which block the cleavage of Notch at the cell membrane and inhibit release of the transcriptionally active NotchIC subunit. Preclinical cancer models have clearly demonstrated that GSIs suppress the growth of such malignancies as pancreatic, breast, and lung cancer; however, GSI treatment in vivo is associated with side effects, especially those within the gastrointestinal tract. Although intensive studies are associated with the role of γ-secretase in pathological states, it should be pointed out that this complex impacts on proteolytic cleavages of around 55 membrane proteins. Therefore, it is clear that GSIs are highly non-specific and additional drugs must be designed, which will more specifically target components of the Notch signalling.
Insights
Notch signalling is crucial for cell fate but can drive cancer. Gamma-secretase inhibitors (GSIs) target this pathway but cause side effects due to lack of specificity.
Area of Science:
- Cellular Biology
- Oncology
- Molecular Signalling
Background:
- Notch signalling is an evolutionarily conserved pathway regulating cell proliferation, differentiation, and apoptosis.
- Overexpression of Notch signalling acts as an oncogene in various human cancers.
- Gamma-secretase inhibitors (GSIs) are explored for cancer therapy by blocking Notch activation.
Purpose of the Study:
- To evaluate the therapeutic potential of targeting Notch signalling in cancer.
- To address the limitations and side effects associated with current gamma-secretase inhibitors.
Main Methods:
- Review of preclinical cancer models demonstrating GSI efficacy.
- Analysis of the mechanism of action for GSIs targeting Notch cleavage.
- Examination of the off-target effects of GSIs due to gamma-secretase non-specificity.
Main Results:
- GSIs show promise in suppressing tumour growth in preclinical models of pancreatic, breast, and lung cancers.
- GSI treatment in vivo is linked to significant gastrointestinal side effects.
- Gamma-secretase, the target of GSIs, cleaves approximately 55 membrane proteins, indicating broad non-specificity.
Conclusions:
- While GSIs demonstrate anti-cancer effects, their non-specific inhibition of gamma-secretase leads to undesirable side effects.
- Development of novel therapeutic agents with higher specificity for Notch pathway components is necessary for effective and safer cancer treatment.
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