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Oligopeptide Competition Assay for Phosphorylation Site Determination
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Energy stress-activated AMPK phosphorylates Snail1 and suppresses its stability and oncogenic function

Mei Li1, Litao Zhang2, Tangming Guan1

  • 1State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan University, Guangzhou, 510632, China.

Cancer Letters
|May 30, 2024
PubMed

Insights

AMP-activated protein kinase (AMPK) activation suppresses triple-negative breast cancer (TNBC) progression by targeting Snail1 degradation. This discovery offers a potential new therapeutic strategy for TNBC management.

Area of Science:

  • Molecular oncology
  • Cancer metabolism
  • Signal transduction

Background:

  • Triple-negative breast cancer (TNBC) is aggressive with limited treatment options.
  • Aberrant cancer metabolism influences tumor progression and therapeutic resistance.
  • The role of glucose metabolism in TNBC progression requires further elucidation.

Purpose of the Study:

  • To investigate the role of aberrant glucose metabolism in regulating Snail1 turnover in TNBC.
  • To identify the mechanisms linking glucose metabolism to Snail1-mediated TNBC progression.
  • To explore the therapeutic potential of targeting this pathway in TNBC.

Main Methods:

  • Investigated the effect of glucose deprivation on Snail1 regulation.
  • Utilized biochemical assays to determine AMP-activated protein kinase (AMPK) phosphorylation of Snail1.
  • Assessed the impact of Snail1 phosphorylation on its interaction with FBXO11 and subsequent degradation.
  • Performed in vitro and in vivo experiments to evaluate the functional consequences of this pathway.
  • Conducted histological analyses of TNBC specimens to correlate p-AMPKα and Snail1 levels.

Main Results:

  • Glucose deprivation activates AMPK, leading to direct phosphorylation of Snail1 at Ser11.
  • Phosphorylated Snail1 is recruited by the E3 ligase FBXO11, promoting its degradation.
  • Suppression of Snail1 by AMPK activation reduces stemness, metastasis, and chemo-resistance in TNBC.
  • Clinical data show an inverse correlation between p-AMPKα and Snail1 in TNBC tissues.

Conclusions:

  • AMPK activation links glucose metabolism to Snail1 degradation, suppressing TNBC stemness, metastasis, and chemo-resistance.
  • This study reveals a novel mechanism regulating Snail1 turnover.
  • AMPK agonists represent a promising therapeutic strategy for TNBC management.
Keywords:
AMPKChemo-resistanceGlucose metabolismMetastasisSnail1Triple-negative breast cancer

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