Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

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.