Checkpoint kinase 1 inhibition sensitises transformed cells to dihydroorotate dehydrogenase inhibition

Stéphanie Arnould 1, 2 Genevieve Rodier 1, 2 Gisèle Matar 2 Charles Vincent 2 Nelly Pirot 2 Yoann Delorme 2 Charlène Berthet 2 Yoan Buscail 2 Jean Yohan Noël 2 Simon Lachambre 3 Marta Jarlier 2 Florence Bernex 4 Hélène Delpech 2 Pierre Olivier Vidalain 5 Yves Janin 6 Charles Theillet 2 Claude Sardet 2
1 IGMM - Institut de Génétique Moléculaire de Montpellier
2 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
3 MRI-Montpellier RIO Imaging
4 UGMC - Génétique Moléculaire et Cellulaire
5 UPD5 Pharmacie - Université Paris Descartes - Faculté de Pharmacie de Paris
6 Chimie et Biocatalyse
Abstract : Reduction in nucleotide pools through the inhibition of mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) has been demonstrated to effectively reduce cancer cell proliferation and tumour growth. The current study sought to investigate whether this antiproliferative effect could be enhanced by combining Chk1 kinase inhibition. The pharmacological activity of DHODH inhibitor teriflunomide was more selective towards transformed mouse embryonic fibroblasts than their primary or immortalised counterparts, and this effect was amplified when cells were subsequently exposed to PF477736 Chk1 inhibitor. Flow cytometry analyses revealed substantial accumulations of cells in S and G2/M phases, followed by increased cytotoxicity which was characterised by caspase 3-dependent induction of cell death. Associating PF477736 with teriflunomide also significantly sensitised SUM159 and HCC1937 human triple negative breast cancer cell lines to dihydroorotate dehydrogenase inhibition. The main characteristic of this effect was the sustained accumulation of teriflunomide-induced DNA damage as cells displayed increased phospho serine 139 H2AX (γH2AX) levels and concentration-dependent phosphorylation of Chk1 on serine 345 upon exposure to the combination as compared with either inhibitor alone. Importantly a similar significant increase in cell death was observed upon dual siRNA mediated depletion of Chk1 and DHODH in both murine and human cancer cell models. Altogether these results suggest that combining DHODH and Chk1 inhibitions may be a strategy worth considering as a potential alternative to conventional chemotherapies.
Keywords : triple negative breast cancer Chk1 DHODH DNA damage cytotoxicity
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https://hal.umontpellier.fr/hal-02291385
Contributeur : Nathalie Salvy-Cordoba <>
Soumis le : mercredi 18 septembre 2019 - 16:37:33
Dernière modification le : lundi 21 octobre 2019 - 21:32:01

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UNIV-MONTPELLIER | INRA | VALDAURELLE | CNRS | FNCLCC | UNIV-PARIS5 | BS | IRCM | USPC | PASTEUR | INC-CNRS

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Stéphanie Arnould, Genevieve Rodier, Gisèle Matar, Charles Vincent, Nelly Pirot, et al.. Checkpoint kinase 1 inhibition sensitises transformed cells to dihydroorotate dehydrogenase inhibition. Oncotarget, Impact journals, 2017, 8 (56), ⟨10.18632/oncotarget.19199⟩. ⟨hal-02291385⟩

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