Journal article
Centrosome Amplification in Cancer Disrupts Autophagy and Sensitizes to Autophagy Inhibition
Molecular cancer research, Vol.18(1), pp.33-45
01/01/2020
DOI: 10.1158/1541-7786.MCR-19-0509
PMCID: PMC6942210
PMID: 31604847
Abstract
Centrosome amplification (CA), or a numerical increase in centrosomes, is common in human cancers, particularly those with high-risk features. We have discovered that cells with CA have an increased burden of autophagy, a catabolic process whereby autophagosomes engulf damaged organelles and proteins and deliver these contents to the lysosome for degradation and subsequent recycling. Cells with CA demonstrate an accumulation of autophagosomes. We evaluated the alternative hypotheses that CA alters autophagy by modulating microtubule networks and impairing trafficking versus altering lysosome clustering and organization versus chromosome missegregation-induced proteotoxic stress. Using LC3 reporter assays and autophagosome tracking experiments, we demonstrate that CA causes an accumulation of autophagosomes by interfering with autophagosome trafficking. To establish whether this was a druggable weakness, we tested autophagy inhibitors in our cell models of CA. Cells with CA are sensitized to chemical and genetic autophagy inhibition. Taken together, our results suggest that autophagy is disrupted by CA and sensitizes cells to inhibition of autophagy. These findings suggest a novel precision medicine strategy, whereby CA increases reliance on autophagy and serves as a biomarker for autophagy inhibitors in high-risk cancers.
Details
- Title: Subtitle
- Centrosome Amplification in Cancer Disrupts Autophagy and Sensitizes to Autophagy Inhibition
- Creators
- Ryan A. Denu - University of Wisconsin–MadisonGulpreet Kaur - University of Wisconsin–MadisonMadilyn M. Sass - University of Wisconsin–MadisonAparna Lakkaraju - University of California, San FranciscoMark E. Burkard - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Molecular cancer research, Vol.18(1), pp.33-45
- DOI
- 10.1158/1541-7786.MCR-19-0509
- PMID
- 31604847
- PMCID
- PMC6942210
- NLM abbreviation
- Mol Cancer Res
- ISSN
- 1541-7786
- eISSN
- 1557-3125
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 13
- Grant note
- F30CA203271; R01 GM097245; R01 EY023299; P30 CA014520 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32GM008692 / University of Wisconsin Medical Scientist Training Program UL1TR000427; TL1TR000429 / University of Wisconsin ICTR TL1 training program (NIH)
- Language
- English
- Date published
- 01/01/2020
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984701259802771
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