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Targeting AVEN Liquid-Liquid Phase Separation in Colorectal Cancer: Insights From a Raddeanin A-Based Chemical Probe.

Xichao Yu1, Hui Wu1, Kezhen Guo1

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Basic & Clinical Pharmacology & Toxicology
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Summary

Apoptosis and caspase activation inhibitor (AVEN) regulates mitochondrial homeostasis in colorectal cancer (CRC) through liquid-liquid phase separation (LLPS). Targeting AVEN with sumatriptan shows therapeutic promise for CRC.

Keywords:
AVENCRCLLPSmitochondrial transfertargeted therapy

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Research

Background:

  • Mitochondrial dysfunction and dysregulated liquid-liquid phase separation (LLPS) are key in colorectal cancer (CRC) pathogenesis.
  • The precise mechanisms and therapeutic targets for these processes remain largely unknown.

Purpose of the Study:

  • To investigate the role of LLPS in mitochondrial dysfunction in CRC.
  • To identify and validate novel therapeutic targets for CRC.

Main Methods:

  • Multi-omics analysis and biophysical assays were employed.
  • Raddeanin A was used as a probe to identify potential targets.
  • In vitro and in vivo models, including mouse models and clinical cohorts, were utilized.

Main Results:

  • Apoptosis and caspase activation inhibitor (AVEN) was identified as a significantly upregulated protein in CRC tissues, localized near mitochondria-endoplasmic reticulum contact sites (MERCS).
  • AVEN undergoes LLPS via its intrinsically disordered regions (IDRs), orchestrating mitochondrial homeostasis by inhibiting apoptosis and facilitating mitochondrial transfer.
  • Sumatriptan (SUM) was identified as a potent inhibitor of AVEN IDRs, demonstrating significant therapeutic efficacy.

Conclusions:

  • AVEN plays a critical role in regulating mitochondrial homeostasis through LLPS in CRC.
  • Targeting AVEN via its IDRs represents a promising therapeutic strategy for colorectal cancer.