Fiche publication
Date publication
juin 2018
Journal
Oncotarget
Auteurs
Membres identifiés du Cancéropôle Est :
Pr HAIECH Jacques
,
Pr HIBERT Marcel
,
Dr VILLA Pascal
,
Dr ZENIOU-MEYER Maria
Tous les auteurs :
Chen W, Zebaze LN, Dong J, Chézeau L, Inquimbert P, Hugel S, Niu S, Bihel F, Boutant E, Réal E, Villa P, Junier MP, Chneiweiss H, Hibert M, Haiech J, Kilhoffer MC, Zeniou M
Lien Pubmed
Résumé
Glioblastoma is a highly heterogeneous brain tumor. The presence of cancer cells with stem-like and tumor initiation/propagation properties contributes to poor prognosis. Glioblastoma cancer stem-like cells (GSC) reside in hypoxic and acidic niches favoring cell quiescence and drug resistance. A high throughput screening recently identified the laxative Bisacodyl as a cytotoxic compound targeting quiescent GSC placed in acidic microenvironments. Bisacodyl activity requires its hydrolysis into DDPM, its pharmacologically active derivative. Bisacodyl was further shown to induce tumor shrinking and increase survival in glioblastoma models. Here we explored the cellular mechanism underlying Bisacodyl cytotoxic effects using quiescent GSC in an acidic microenvironment and GSC-derived 3D macro-spheres. These spheres mimic many aspects of glioblastoma tumors , including hypoxic/acidic areas containing quiescent cells. Phosphokinase protein arrays combined with pharmacological and genetic modulation of signaling pathways point to the WNK1 serine/threonine protein kinase as a mediator of Bisacodyl cytotoxic effect in both cell models. WNK1 partners including the Akt and SGK1 protein kinases and NBC-family Na/HCO3 cotransporters were shown to participate in the compound's effect on GSC. Overall, our findings uncover novel potential therapeutic targets for combatting glioblastoma which is presently an incurable disease.
Mots clés
Akt/SGK1, Bisacodyl/DDPM, NBC Na+/HCO3− cotransporters, WNK1, glioblastoma cancer stem-like cells
Référence
Oncotarget. 2018 Jun 5;9(43):27197-27219
