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Updated: Oct 13, 2025

Live-Cell Förster Resonance Energy Transfer Imaging of Metabolically Regulated Akt Activation Dynamics in HepG2 Cells
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Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT.

Mahamat Babagana1, Lorin R Brown1, Hannah Z Slabodkin1

  • 1Roswell Park Comprehensive Cancer Center, Department of Cell Stress Biology, Buffalo, NY 14263, USA.

International Journal of Molecular Sciences
|November 13, 2021
PubMed
Summary

Hyperactive AKT (a serine-threonine kinase) causes proteotoxic stress, making cancer cells vulnerable. This stress can be targeted by increasing it or reducing cellular tolerance mechanisms for cancer therapy.

Keywords:
AKTHSF1HSP70HSP90PTENXBP1heat shock

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • Hyperactivity of serine-threonine kinase AKT is common in cancer, promoting malignant cell growth and survival.
  • AKT hyperactivity, despite its anti-apoptotic role, induces cellular stress.

Purpose of the Study:

  • To investigate the signs of proteotoxic stress in cancer cells with hyperactive AKT or PTEN loss.
  • To understand the role of HSF1 and XBP1 in mediating this stress response.

Main Methods:

  • Observation of proteotoxic stress markers in cells with hyperactive AKT or PTEN deficiency.
  • Assessment of heat shock sensitivity in normal, HSF1-deficient, and AKT-hyperactive cells.
  • Quantification of XBP1 levels and growth dependency in AKT-hyperactive cells.

Main Results:

  • Cells with hyperactive AKT or PTEN loss showed elevated heat shock sensitivity and increased HSF1 activity.
  • Hyperactive AKT increased XBP1 levels, a key component of proteotoxic stress defense.
  • Cancer cells with hyperactive AKT exhibited increased dependency on XBP1 for growth.

Conclusions:

  • Proteotoxic stress induced by hyperactive AKT represents a targetable vulnerability in cancer.
  • Therapeutic strategies could involve increasing this stress or inhibiting tolerance pathways like XBP1.