ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress

Area of Science:

• Oncology
• Molecular Biology
• Cellular Stress Response

Background:

• Colon cancer is a leading cause of cancer death, often becoming aggressive and treatment-resistant.
• The Unfolded Protein Response (UPR) and DNA Damage Response (DDR) are critical cellular adaptive mechanisms.
• While UPR sensors IRE1 alpha and PERK are linked to DDR, the role of ATF6 remains less understood.

Purpose of the Study:

• To investigate the role of the ATF6 UPR sensor in colon cancer.
• To determine if ATF6 influences DNA Damage Response (DDR) pathways.
• To explore ATF6 as a potential therapeutic target in colon cancer treatment.

Main Methods:

• Investigated ATF6's role in colon cancer cell lines.
• Utilized ER stressors (DPE, Thapsigargin) and Adriamycin.
• Assessed BRCA-1 expression, DNA damage markers, and cell viability.
• Examined the molecular mechanism involving mTOR and HSP90.

Main Results:

• ATF6 was found to sustain BRCA-1 expression, protecting colon cancer cells from ER stressors.
• ATF6 activates mTOR, which in turn supports HSP90-mediated BRCA-1 stability.
• Inhibition of ATF6 led to BRCA-1 degradation, increased DNA damage, and cell death, especially when combined with Adriamycin.

Conclusions:

• ATF6 plays a protective role in colon cancer by maintaining BRCA-1 expression.
• Targeting ATF6 enhances sensitivity to DNA damaging agents like Adriamycin.
• Inhibiting ATF6 represents a promising strategy to overcome chemoresistance in colon cancer.