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Neddylation Pathway as a Novel Anti-cancer Target: Mechanistic Investigation and Therapeutic Implication

Yanan Jiang, Lijun Jia1

  • 1Cancer Institute, Fudan University Shanghai Cancer Center, 270 DongAn Road, Shanghai, 200032, China. ljjia@fudan.edu.cn.

Anti-Cancer Agents in Medicinal Chemistry
|March 6, 2015
PubMed

Insights

Protein neddylation, a process involving the addition of NEDD8 to substrates, is crucial for biological functions. Inhibiting this pathway, particularly with MLN4924, shows promise as an anticancer strategy by targeting cancer and its microenvironment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Protein neddylation, a posttranslational modification involving NEDD8 conjugation, regulates vital biological processes.
  • Dysregulation of neddylation is implicated in various diseases, notably cancer.
  • The tumor microenvironment (TME) is increasingly recognized as a key regulator of cancer progression.

Purpose of the Study:

  • To review recent advancements in understanding the role of protein neddylation in cancer.
  • To highlight the neddylation pathway as a potential therapeutic target for human cancers.
  • To explore the impact of neddylation on the tumor microenvironment.

Main Methods:

  • Literature review of recent studies on protein neddylation and cancer.
  • Analysis of the mechanism of action of NEDD8-activating enzyme (NAE) inhibitors, such as MLN4924.
  • Examination of evidence linking neddylation to tumor angiogenesis and immune cell function within the TME.

Main Results:

  • Inhibition of the neddylation pathway, exemplified by NAE inhibitor MLN4924, demonstrates potent anticancer efficacy.
  • MLN4924 has shown favorable tolerability in Phase I clinical trials for various cancers.
  • Emerging evidence reveals the critical role of neddylation in regulating TME components, including angiogenesis and immune responses.

Conclusions:

  • The neddylation pathway is a significant regulator of cancer development and progression.
  • Targeting protein neddylation represents a promising therapeutic strategy for cancer treatment.
  • Further research into neddylation's role in the TME could unveil novel anticancer approaches.

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