Saltar al contenido
Merck

Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51.

Cell death and differentiation (2021-02-04)
Gwenola Manic, Martina Musella, Francesca Corradi, Antonella Sistigu, Sara Vitale, Sara Soliman Abdel Rehim, Luca Mattiello, Eva Malacaria, Claudia Galassi, Michele Signore, Matteo Pallocca, Stefano Scalera, Frauke Goeman, Francesca De Nicola, Andrea Guarracino, Rosa Pennisi, Fabrizio Antonangeli, Francesca Sperati, Marta Baiocchi, Mauro Biffoni, Maurizio Fanciulli, Marcello Maugeri-Saccà, Annapaola Franchitto, Pietro Pichierri, Ruggero De Maria, Ilio Vitale
RESUMEN

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.

MATERIALES
Referencia del producto
Marca
Descripción del producto

Sigma-Aldrich
Anticuerpo anti-fosfo-histona H2A.X (Ser139), clon JBW301, clone JBW301, Upstate®, from mouse
Sigma-Aldrich
(±)-Verapamil hydrochloride, ≥99% (titration), powder
Sigma-Aldrich
Chk2 Inhibitor, PV1019, The Chk2 Inhibitor, PV1019 controls the biological activity of Chk2. This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications.