Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction

Area of Science:

• Cancer Biology
• Molecular Oncology
• Genetics

Background:

• The tumor suppressor gene PTEN is frequently deleted in various cancers, often encompassing adjacent genes on chromosome 10q23.
• Co-deletion of PTEN-adjacent genes can create unique cancer cell vulnerabilities with potential therapeutic implications.

Purpose of the Study:

• To investigate the functional role of ATAD1, a gene adjacent to PTEN and frequently co-deleted in cancer.
• To determine if ATAD1 loss influences cancer cell sensitivity to therapeutic interventions.

Main Methods:

• Analysis of chromosome 10q23 deletions and their impact on adjacent genes, including ATAD1.
• Functional studies in cultured cells and mouse xenografts to assess apoptosis induction and drug sensitivity.
• Investigation of ATAD1's interaction with the pro-apoptotic protein BIM and mitochondrial localization.

Main Results:

• Loss of ATAD1 predisposes cancer cells to apoptosis induced by proteasome dysfunction.
• ATAD1 directly extracts and inactivates the pro-apoptotic protein BIM from mitochondria.
• ATAD1-deficient cancer cells and xenografts exhibit hypersensitivity to proteasome inhibitors, leading to BIM activation and apoptosis.
• Loss of ATAD1 correlates with improved survival in cancer patients.

Conclusions:

• The loss of ATAD1, frequently co-deleted with PTEN, represents a therapeutic vulnerability in cancers with 10q23 deletions.
• Targeting proteasome dysfunction offers a potential treatment strategy for these patients.
• Understanding ATAD1's role in mitochondrial protein homeostasis opens new avenues for cancer therapy.