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Review
. 2010 Dec;1806(2):258-67.
doi: 10.1016/j.bbcan.2010.06.001. Epub 2010 Jun 22.

Targeting Notch signaling pathway to overcome drug resistance for cancer therapy

Zhiwei Wang  1 , Yiwei Li, Aamir Ahmad, Asfar S Azmi, Sanjeev Banerjee, Dejuan Kong, Fazlul H Sarkar
Affiliations
Review

Targeting Notch signaling pathway to overcome drug resistance for cancer therapy

Zhiwei Wang et al. Biochim Biophys Acta. 2010 Dec.

Abstract

Chemotherapy is an important therapeutic strategy for cancer treatment and remains the mainstay for the management of human malignancies; however, chemotherapy fails to eliminate all tumor cells because of intrinsic or acquired drug resistance, which is the most common cause of tumor recurrence. Recently, emerging evidences suggest that Notch signaling pathway is one of the most important signaling pathways in drug-resistant tumor cells. Moreover, down-regulation of Notch pathway could induce drug sensitivity, leading to increased inhibition of cancer cell growth, invasion, and metastasis. This article will provide a brief overview of the published evidences in support of the roles of Notch in drug resistance and will further summarize how targeting Notch by "natural agents" could become a novel and safer approach for the improvement of tumor treatment by overcoming drug resistance.

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Figures

Figure-1
Figure-1. A, Structure of Notch receptors (1-4) and ligands (Jagged-1, 2, Dll-1, 3, 4)
Both receptors and ligands contain multiple conserved domains. Notch is a single-pass transmembrane receptor. The extracellular domain contains EGF-like repeats and a cysteine-rich region. The intracellular domain contains the RAM domain, NLS, ANK, TAD and PEST domain. Notch ligands have multiple EGF-like repeats in their extracellular domain and a CR in Jagged which are absent in Delta. B, Schematic of Notch signaling. Notch signaling is activated after ligand binding to an adjacent Notch receptor between two neighboring cells. Upon activation, Notch receptors undergo a series of proteolytic cleavages by the metalloprotease, TACE, and γ-secretase complex. The cleavage releases the NICD into the cytoplasm, which can subsequently translocate into the nucleus. In the absence of NICD, transcription of Notch target genes is inhibited by a repressor complex mediated by the CSL. When NICD is in the nucleus, it forms an active transcriptional complex due to displacing the histone deacetylase-corepressor complex and recruiting the protein MAML1 and histone acetyltransferases to the CSL complex, leading to convert it from a transcriptional repressor into a transcription activator complex, leading to activation of Notch target genes. Diagram of putative therapeutic target in the Notch pathway. Notch signaling could be inhibited theoretically at many different levels. It is possible to (1) interfere with Notch-ligand interactions, (2) inhibit receptor activation, (3) promote Notch ubiquitination and degradation, (4) inhibit its translocation to the nuclear compartment and (5) inhibit NICD nuclear complex formation. ANK: Ankyrin repeat, CR: Cysteine rich region, DSL: Delta-serrate-lag2, EGF: Epidermal growth factor, LNR: Lin12/Notch repeats, NLS: Nuclear localization signals, PEST: Proline, glutamine, serine,threonine, RAM: RBP-J association molecule domain, TAD: Transcriptional activator domain, TM: Transmembrane domain. CSL: C protein binding factor 1/Suppressor of Hairless/Lag-1, NICD: Notch intracellular domain, TACE: tumor necrosis factor-α-converting enzyme, MAML1: mastermind-like 1.
Figure-2
Figure-2
The role of Notch signaling pathway in the progression of cancer, and during the acquisition of EMT phenotype, and the formation of cancer stem cells, leading to drug resistance. Natural agents and γ-secretase inhibitors could be useful for targeting Notch signaling pathway proteins, which could enhance the sensitivity of chemotherapeutic drugs.
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