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The 14-3-3σ/GSK3β/β-catenin/ZEB1 regulatory loop modulates chemo-sensitivity in human tongue cancer

Cong Peng1, Xiaoting Jia1, Yan Xiong2

  • 1Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.

Oncotarget
|June 4, 2015
PubMed

Insights

Chemotherapy increases 14-3-3σ expression in tongue cancer (TC) cells, enhancing sensitivity, particularly in multidrug-resistant (MDR-TC) cells. This involves the 14-3-3σ/GSK3β/β-catenin pathway, with higher 14-3-3σ and GSK3β linked to better patient prognosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • 14-3-3σ plays a role in cellular responses to stress and DNA damage.
  • Chemotherapy resistance remains a significant challenge in treating tongue cancer (TC).
  • The 14-3-3σ/GSK3β/β-catenin signaling axis is implicated in various cancers.

Purpose of the Study:

  • To investigate the role of 14-3-3σ in chemotherapy sensitivity in tongue cancer.
  • To elucidate the molecular mechanisms underlying 14-3-3σ's function in TC chemotherapy response.
  • To explore the relationship between 14-3-3σ, GSK3β, β-catenin, and ZEB1 in multidrug-resistant TC (MDR-TC).

Main Methods:

  • Cell culture and treatment of TC and MDR-TC cell lines.
  • Western blotting and immunoprecipitation to assess protein interactions and levels.
  • Quantitative real-time PCR and methylation-specific PCR to analyze gene expression and promoter methylation.
  • Analysis of patient tissue samples for protein expression correlation.

Main Results:

  • Chemotherapy induced 14-3-3σ expression in TC cells, sensitizing them to treatment, especially MDR-TC cells.
  • 14-3-3σ physically bound to GSK3β, inhibiting β-catenin signaling and increasing GSK3β levels, which enhanced chemotherapy sensitivity.
  • Deregulation of the 14-3-3σ/GSK3β/β-catenin axis led to ZEB1 overexpression, which promoted 14-3-3σ promoter hypermethylation and reduced 14-3-3σ expression.
  • Positive correlation between 14-3-3σ and GSK3β expression in patient tissues, associated with better prognosis.

Conclusions:

  • 14-3-3σ acts as a crucial sensitizer to chemotherapy in tongue cancer by modulating the GSK3β/β-catenin pathway.
  • ZEB1-induced hypermethylation of the 14-3-3σ promoter represents a negative feedback loop contributing to chemoresistance.
  • Elevated 14-3-3σ and GSK3β levels are promising biomarkers for predicting better treatment outcomes in TC patients receiving chemotherapy.
Keywords:
14-3-3σGSK3βchemosensitivitytongue cancerβ-catenin

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