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Reduced replication origin licensing selectively kills KRAS-mutant colorectal cancer cells via mitotic catastrophe.
- Source :
-
Cell death & disease [Cell Death Dis] 2020 Jul 01; Vol. 11 (7), pp. 499. Date of Electronic Publication: 2020 Jul 01. - Publication Year :
- 2020
-
Abstract
- To unravel vulnerabilities of KRAS-mutant CRC cells, a shRNA-based screen specifically inhibiting MAPK pathway components and targets was performed in CaCo2 cells harboring conditional oncogenic KRAS <superscript>G12V</superscript> . The custom-designed shRNA library comprised 121 selected genes, which were previously identified to be strongly regulated in response to MEK inhibition. The screen showed that CaCo2 cells expressing KRAS <superscript>G12V</superscript> were sensitive to the suppression of the DNA replication licensing factor minichromosome maintenance complex component 7 (MCM7), whereas KRAS <superscript>wt</superscript> CaCo2 cells were largely resistant to MCM7 suppression. Similar results were obtained in an isogenic DLD-1 cell culture model. Knockdown of MCM7 in a KRAS-mutant background led to replication stress as indicated by increased nuclear RPA focalization. Further investigation showed a significant increase in mitotic cells after simultaneous MCM7 knockdown and KRAS <superscript>G12V</superscript> expression. The increased percentage of mitotic cells coincided with strongly increased DNA damage in mitosis. Taken together, the accumulation of DNA damage in mitotic cells is due to replication stress that remained unresolved, which results in mitotic catastrophe and cell death. In summary, the data show a vulnerability of KRAS-mutant cells towards suppression of MCM7 and suggest that inhibiting DNA replication licensing might be a viable strategy to target KRAS-mutant cancers.
- Subjects :
- Caco-2 Cells
Cell Death
Cell Proliferation
Cellular Senescence
DNA Damage
DNA Replication
Gene Knockdown Techniques
Humans
Minichromosome Maintenance Complex Component 7 metabolism
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
Mitosis
Mutation genetics
Proto-Oncogene Proteins p21(ras) genetics
Replication Origin
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 11
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 32612138
- Full Text :
- https://doi.org/10.1038/s41419-020-2704-9