Sen Plaboni, Ghosh Siddhartha Sankar
Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
Centre for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
ACS Pharmacol Transl Sci. 2023 May 3;6(5):651-670. doi: 10.1021/acsptsci.2c00239. eCollection 2023 May 12.
The Notch pathway is remarkably simple without the interventions of secondary messengers. It possesses a unique receptor-ligand interaction that imparts signaling upon cleavage of the receptor followed by the nuclear localization of its cleaved intracellular domain. It is found that the transcriptional regulator of the Notch pathway lies at the intersection of multiple signaling pathways that enhance the aggressiveness of cancer. The preclinical and clinical evidence supports the pro-oncogenic function of Notch signaling in various tumor subtypes. Owing to its oncogenic role, the Notch signaling pathway assists in enhanced tumorigenesis by facilitating angiogenesis, drug resistance, epithelial to mesenchymal transition, etc., which is also attributed to the poor outcome in patients. Therefore, it is extremely vital to discover a suitable inhibitor to downregulate the signal-transducing ability of Notch. The Notch inhibitory agents, such as receptor decoys, protease (ADAM and γ-secretase) inhibitors, and monoclonal/bispecific antibodies, are being investigated as candidate therapeutic agents. Studies conducted by our group exemplify the promising results in ablating tumorigenic aggressiveness by inhibiting the constituents of the Notch pathway. This review deals with the detailed mechanism of the Notch pathways and their implications in various malignancies. It also bestows us with the recent therapeutic advances concerning Notch signaling in the context of monotherapy and combination therapy.
Notch信号通路非常简单，无需二级信使的干预。它具有独特的受体 - 配体相互作用，在受体裂解后赋予信号传导能力，随后其裂解的细胞内结构域进行核定位。研究发现，Notch信号通路的转录调节因子位于多个增强癌症侵袭性的信号通路的交叉点。临床前和临床证据支持Notch信号在各种肿瘤亚型中的促癌功能。由于其致癌作用，Notch信号通路通过促进血管生成、耐药性、上皮 - 间质转化等协助增强肿瘤发生，这也归因于患者的不良预后。因此，发现合适的抑制剂来下调Notch的信号转导能力至关重要。Notch抑制剂，如受体诱饵、蛋白酶（ADAM和γ-分泌酶）抑制剂以及单克隆/双特异性抗体，正在作为候选治疗药物进行研究。我们小组进行的研究例证了通过抑制Notch信号通路的组成成分来消除肿瘤发生侵袭性的有前景的结果。这篇综述探讨了Notch信号通路的详细机制及其在各种恶性肿瘤中的影响。它还为我们提供了在单药治疗和联合治疗背景下关于Notch信号传导的最新治疗进展。
