Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction
Abstract
The tumor suppressor gene PTEN is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of PTEN itself, which frequently disrupts adjacent genes. Coincidental loss of PTEN-adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here we describe how the loss of ATAD1, which is adjacent to and frequently co-deleted with PTEN, predisposes cancer cells to apoptosis triggered by proteasome dysfunction and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic protein BIM from mitochondria to inactivate it. Cultured cells and mouse xenografts lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which activate BIM and trigger apoptosis. This work furthers our understanding of mitochondrial protein homeostasis and could lead to new therapeutic options for the hundreds of thousands of cancer patients who have tumors with chromosome 10q23 deletion.
Data availability
All data and source data generated or analyzed are included as supplementary files. CRISPR screening data and human mCRPC survival data are provided as supplementary files.
Article and author information
Author details
Funding
National Institutes of Health (1F30CA243440)
- Jacob M Winter
Howard Hughes Medical Institute
- Jared Rutter
National Institutes of Health (1T32DK11096601)
- Jordan A Berg
National Institutes of Health (1F99CA253744)
- Jordan A Berg
National Institutes of Health (5T32DK091317)
- Corey N Cunningham
National Institutes of Health (1F32GM140525)
- Corey N Cunningham
National Institutes of Health (K00CA212445)
- Alex J Bott
National Institutes of Health (R35GM137904)
- Matthew L Wohlever
National Institutes of Health (CA228346)
- Jared Rutter
National Institutes of Health (R35GM131854)
- Jared Rutter
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Erica A Golemis, Fox Chase Cancer Center, United States
Ethics
Animal experimentation: All of the animals were handled according to approved institutional animal care and use committee (IACUC protocol # 18-11004) protocols of the University of Utah. Every effort was made to minimize suffering.
Version history
- Preprint posted: July 3, 2021 (view preprint)
- Received: August 20, 2022
- Accepted: November 20, 2022
- Accepted Manuscript published: November 21, 2022 (version 1)
- Version of Record published: January 5, 2023 (version 2)
- Version of Record updated: January 10, 2023 (version 3)
Copyright
© 2022, Winter et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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