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Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer

Boopathi Subramaniyan1, Sangita Sridharan1, Cory M Howard1

  • 1Department of Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA.

Cancers
|August 23, 2020
PubMed

Insights

The CXCL12-CXCR4 pathway stabilizes nuclear Snail1 via LIM and SH3 protein 1 (LASP1) in triple-negative breast cancer. This axis regulates key proteins, impacting cancer cell invasion and stem-like properties.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The CXCL12-CXCR4 axis is crucial for breast cancer metastasis, but its precise molecular mechanisms remain unclear.
  • Previous work established that CXCL12-induced CXCR4 activation leads to nuclear LIM and SH3 protein 1 (LASP1) localization and interaction with Snail1 in triple-negative breast cancer (TNBC).

Purpose of the Study:

  • To elucidate the molecular mechanisms by which the CXCL12-CXCR4 axis influences Snail1 stability and breast cancer metastasis.
  • To investigate the role of nuclear LASP1 in regulating nuclear Snail1 accumulation and its downstream effects in TNBC.

Main Methods:

  • Utilized triple-negative breast cancer cell lines.
  • Investigated protein-protein interactions and localization using molecular biology techniques.
  • Performed genetic ablation of LASP1 to assess its functional impact.
  • Analyzed the expression of epithelial and mesenchymal markers, including ALDH1A1.

Main Results:

  • Nuclear accumulation and retention of Snail1 were dependent on increased nuclear LASP1 levels, driven by active CXCR4.
  • The CXCR4-LASP1 axis regulates the stabilization of nuclear Snail1 by upregulating nuclear pS473-Akt, pS9-GSK-3β, A20, and LSD1.
  • Genetic ablation of LASP1 caused Snail1 mislocalization, reduced Matrigel invasion, and altered expression of epithelial/mesenchymal markers, including increased ALDH1A1.

Conclusions:

  • The CXCR4-LASP1 axis plays a novel role in stabilizing nuclear Snail1, potentially through direct regulation of key proteins and protein-protein interactions.
  • This axis is critical for maintaining Snail1 stability, influencing TNBC cell invasion and stem-like characteristics.
Keywords:
A20AktCXCR4GSK-3βLASP1Snail1 stability

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