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Published on: March 27, 2020

Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit

C L Neal1, J Xu, P Li

  • 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Oncogene
|July 12, 2011
PubMed

Insights

Overexpression of 14-3-3ζ protein boosts Akt phosphorylation, a key driver in breast cancer progression and recurrence. This mechanism involves 14-3-3ζ activating phosphoinositide 3-kinase (PI3K).

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • 14-3-3 proteins are crucial regulators of cellular pathways involved in cancer development.
  • Previous studies indicated 14-3-3ζ overexpression elevates Akt phosphorylation in mammary epithelial cells.

Purpose of the Study:

  • To explore the clinical significance of 14-3-3ζ-mediated Akt phosphorylation in breast cancer.
  • To elucidate the molecular mechanisms underlying this pathway and its role in tumor progression.

Main Methods:

  • Assessed 14-3-3ζ and Akt phosphorylation levels in human breast tumors.
  • Utilized small interfering RNA to knockdown 14-3-3ζ expression in cancer cell lines and xenografts.
  • Investigated the interaction between 14-3-3ζ and the p85 subunit of phosphoinositide 3-kinase (PI3K).
  • Performed site-directed mutagenesis on serine 83 of the p85 subunit.

Main Results:

  • 14-3-3ζ overexpression strongly correlated with increased Akt phosphorylation in breast tumors (P=0.005).
  • Combined 14-3-3ζ overexpression and high Akt phosphorylation linked to higher cancer recurrence rates (P=0.01).
  • Knockdown of 14-3-3ζ reduced Akt phosphorylation.
  • 14-3-3ζ enhances PI3K activation by binding to its p85 subunit and promoting membrane translocation.
  • Mutation of serine 83 on p85 abrogated 14-3-3ζ binding, PI3K activation, and impaired tumor growth.

Conclusions:

  • 14-3-3ζ overexpression activates the PI3K/Akt pathway, contributing to breast cancer progression and recurrence.
  • The interaction between 14-3-3ζ and serine 83 on the PI3K p85 subunit is critical for this oncogenic signaling.
  • Targeting the 14-3-3ζ-PI3K interaction may offer a therapeutic strategy for breast cancer.

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