Back to Search
Start Over
Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2021 Jul; Vol. 28 (7), pp. 2060-2082. Date of Electronic Publication: 2021 Feb 02. - Publication Year :
- 2021
-
Abstract
- Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations.
- Subjects :
- Antineoplastic Agents pharmacology
Cell Line, Tumor
Colorectal Neoplasms genetics
DNA Replication drug effects
Humans
MRE11 Homologue Protein genetics
Neoplastic Stem Cells metabolism
Poly (ADP-Ribose) Polymerase-1 genetics
Rad51 Recombinase genetics
Colorectal Neoplasms drug therapy
MRE11 Homologue Protein drug effects
Mitosis drug effects
Neoplastic Stem Cells drug effects
Poly (ADP-Ribose) Polymerase-1 drug effects
Rad51 Recombinase drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5403
- Volume :
- 28
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 33531658
- Full Text :
- https://doi.org/10.1038/s41418-020-00733-4