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XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling

Xing Huang1, Zhengsheng Wu, Yide Mei

  • 1Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.

The EMBO Journal
|June 11, 2013
PubMed

Insights

X-linked inhibitor of apoptosis (XIAP) suppresses autophagy via Mdm2, impacting p53 regulation. This XIAP-Mdm2-p53 pathway inhibition of autophagy promotes tumor growth, as seen in mouse models and human cancer samples.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • Autophagy is crucial for starvation adaptation, but its inhibition is implicated in tumorigenesis.
  • X-linked inhibitor of apoptosis (XIAP) is upregulated in various cancers, with unclear mechanisms.
  • Understanding XIAP's role in cancer progression is vital.

Purpose of the Study:

  • To elucidate the mechanism by which XIAP influences autophagy.
  • To investigate the role of XIAP-mediated autophagy inhibition in tumorigenesis.
  • To identify novel therapeutic targets in XIAP-associated cancers.

Main Methods:

  • Investigated XIAP's ubiquitin E3 ligase activity towards Mdm2.
  • Analyzed autophagy regulation downstream of the PI3K/Akt pathway.
  • Utilized mouse models (HCT116 cells) and clinical tumor samples to validate findings.

Main Results:

  • XIAP suppresses autophagy through its E3 ligase activity on Mdm2, a p53 regulator.
  • XIAP controls autophagy induction by serum starvation, acting downstream of PI3K/Akt.
  • XIAP-induced autophagy inhibition promotes tumor formation in mouse models.
  • XIAP-mediated autophagy suppression is confirmed in clinical tumor samples.

Conclusions:

  • A novel XIAP-Mdm2-p53 pathway inhibits autophagy.
  • XIAP contributes to tumorigenesis by suppressing autophagy.
  • This pathway represents a potential therapeutic target for XIAP-associated cancers.

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