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The metastasis suppressor protein NM23-H1 modulates the PI3K-AKT axis through interaction with the p110α catalytic

Francesco Paolo Pennino1, Masanao Murakami2, Massimo Zollo3,4,5

  • 1Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, Tumor Virology Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.

Oncogenesis
|May 1, 2021
PubMed

Insights

The metastasis suppressor NM23-H1 interacts with PI3K p110α, inhibiting cancer cell migration and invasion. This interaction negatively correlates with Akt phosphorylation, a key marker of PI3K pathway activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The phosphatidylinositol 3-kinase (PI3K) pathway is frequently dysregulated in cancer, often due to mutations in the PI3KCA gene encoding the p110α catalytic subunit.
  • The metastasis suppressor protein NM23-H1 (NME1) is known to inhibit tumor metastasis and has been implicated in regulating phosphatidylinositol signaling.

Purpose of the Study:

  • To investigate the interaction between NM23-H1 and the p110α subunit of PI3K.
  • To elucidate the functional consequences of this interaction on PI3K pathway activation and cancer cell behavior.

Main Methods:

  • Co-immunoprecipitation to detect protein interactions.
  • Immunofluorescence microscopy to determine subcellular localization of NM23-H1 and p110α.
  • Western blotting to assess Akt phosphorylation levels.
  • Cell motility, invasion, adhesion, and clonogenicity assays to evaluate functional consequences.
  • Analysis of NM23-H1 mutants to assess the role of enzymatic and metastasis suppressor activities.

Main Results:

  • NM23-H1 directly interacts with the p110α subunit of PI3K, primarily at the plasma membrane.
  • NM23-H1 expression inversely correlates with Akt phosphorylation, indicating inhibition of PI3K pathway activation.
  • NM23-H1 suppresses p110α-driven increases in cell migration, invasion, adhesion, and filopodia formation.
  • NM23-H1 mutants lacking enzymatic or metastasis suppressor activity do not interact with p110α or affect the PI3K-AKT axis.

Conclusions:

  • NM23-H1 acts as a negative regulator of the PI3K/Akt pathway by interacting with p110α.
  • This interaction inhibits key oncogenic processes including cell migration, invasion, and anchorage-independent growth.
  • NM23-H1's metastasis suppressor function is linked to its ability to inhibit PI3K signaling.

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