Jihu Dong

Centre National de la Recherche Scientifique

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Maria Zeniou

Université de Strasbourg

Jacques Haiech

Centre National de la Recherche Scientifique

Marie‐Claude Kilhoffer

Université de Strasbourg

Wanyin Chen

Jiangsu University

Hervé Chneiweiss

Inserm

Marie‐Pierre Junier

Institut de Biologie Paris-Seine

Marie Fève

Université de Strasbourg

Dieudonné Emmanuel Pegnyemb

Université de Yaoundé I

Elias A. El-Habr

Institut de Biologie Paris-Seine

Christophe Salomé

Philochem (Switzerland)

Cooperative Institutions

Centre National de la Recherche Scientifique

Université de Strasbourg

Laboratoire d'Innovation Thérapeutique

Inserm

École Supérieure de Biotechnologie de Strasbourg

Institut Polytechnique de Bordeaux

Laboratoire de Biophotonique et Pharmacologie

Université Paris Cité

Institut Pluridisciplinaire Hubert Curien

Sorbonne Université

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Quiescence status of glioblastoma stem-like cells involves remodelling of Ca2+ signalling and mitochondrial shape

Scientific Reports (2018)

Francisco J. Aulestia Isabelle Néant Jihu Dong Jacques Haiech Marie‐Claude Kilhoffer

Quiescence is a reversible cell-cycle arrest which allows cancer stem-like cells to evade killing following therapies. Here, we show that proliferating glioblastoma stem-like cells (GSLCs) can be induced and maintained in a quiescent state by lowering the extracellular pH. Through RNAseq analysis we identified Ca2+ signalling genes differentially expressed between proliferating and quiescent GSLCs. Using the bioluminescent Ca2+ reporter EGFP-aequorin we observed that the changes in Ca2+ homeostasis occurring during the switch from proliferation to quiescence are controlled through store-operated channels (SOC) since inhibition of SOC drives proliferating GSLCs to quiescence. We showed that this switch is characterized by an increased capacity of GSLCs' mitochondria to capture Ca2+ and by a dramatic and reversible change of mitochondrial morphology from a tubular to a donut shape. Our data suggest that the remodelling of the Ca2+ homeostasis and the reshaping of mitochondria might favours quiescent GSLCs' survival and their aggressiveness in glioblastoma.

Aequorin

Homeostasis

Calcium Signaling

10.1038/s41598-018-28157-8

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Physiopathology of cancer stern cells isolated from primary glioblastoma and pre-clinical evaluation of lead molecules by an approach of biology and medicinal chemistry

HAL (Le Centre pour la Communication Scientifique Directe) (2015)

Jihu Dong

Stern

Brain cancer

Primary (astronomy)

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WNK1 kinase and its partners Akt, SGK1 and NBC-family Na+/HCO3− cotransporters are potential therapeutic targets for glioblastoma stem-like cells linked to Bisacodyl signaling

Oncotarget (2018)

Wanyin Chen Leonel Nguekeu Zebaze Jihu Dong Laëtitia Chézeau Perrine Inquimbert

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 in vivo 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 in vivo, 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.

10.18632/oncotarget.25509

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Cancer Stem Cell Quiescence and Plasticity as Major Challenges in Cancer Therapy

Stem Cells International (2016)

Wanyin Chen Jihu Dong Jacques Haiech Marie‐Claude Kilhoffer Maria Zeniou

Cells with stem-like properties, tumorigenic potential, and treatment-resistant phenotypes have been identified in many human malignancies. Based on the properties they share with nonneoplastic stem cells or their ability to initiate and propagate tumors in vivo , such cells were designated as cancer stem (stem-like) or tumor initiating/propagating cells. Owing to their implication in treatment resistance, cancer stem cells (CSCs) have been the subject of intense investigation in past years. Comprehension of CSCs’ intrinsic properties and mechanisms they develop to survive and even enhance their aggressive phenotype within the hostile conditions of the tumor microenvironment has reoriented therapeutic strategies to fight cancer. This report provides selected examples of malignancies in which the presence of CSCs has been evidenced and briefly discusses methods to identify, isolate, and functionally characterize the CSC subpopulation of cancer cells. Relevant biological targets in CSCs, their link to treatment resistance, proposed targeting strategies, and limitations of these approaches are presented. Two major aspects of CSC physiopathology, namely, relative in vivo quiescence and plasticity in response to microenvironmental cues or treatment, are highlighted. Implications of these findings in the context of the development of new therapies are discussed.

10.1155/2016/1740936

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Bisacodyl stability in GSCs’ culture media.

Maria Zeniou Marie Fève Samir Mameri Jihu Dong Christophe Salomé

Bisacodyl

10.1371/journal.pone.0134793.g008

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Triterpenoid saponins from Albizia boromoensis Aubrév. & Pellegr

Phytochemistry Letters (2014)

Olivier Placide Noté Jihu Dong Cyril Antheaume Dominique Guillaume Dieudonné Emmanuel Pegnyemb

Phytochemical

DEPT

Oleanane

Albizia

10.1016/j.phytol.2014.11.004

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Citations (9)

Beta-galactosidase in complex with PETG

M. Saur Michael J. Hartshorn Jihu Dong Judith Reeks G. Bunkóczi

10.2210/pdb6tte/pdb

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Bisacodyl and its cytotoxic activity on human glioblastoma stem-like cells. Implication of inositol 1,4,5-triphosphate receptor dependent calcium signaling

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (2017)

Jihu Dong Francisco J. Aulestia Suzana Assad Kahn Maria Zeniou Luiz Gustavo Dubois

Neurosphere

10.1016/j.bbamcr.2017.01.010

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Citations (17)

Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells

PLoS ONE (2015)

Maria Zeniou Marie Fève Samir Mameri Jihu Dong Christophe Salomé

Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM), the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication.

Bisacodyl

10.1371/journal.pone.0134793

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Physiopathologie de cellules souches cancéreuses isolées de glioblastomes primitifs et évaluation pré-clinique de molécules "tête de série" par une approche de biologie et de chimie médicinale

Jihu Dong

Les glioblastomes sont des tumeurs primaires du cerveau les plus malignes. L’identification des cellules souches cancereuses de glioblastome (CSGs) a transforme notre vision globale des glioblastomes en revelant une hierarchie cellulaire au sein de ces tumeurs. Les CSGs sont douees de proprietes d’auto-renouvellement, de differenciation et peuvent entrer en quiescence. Elles sont considerees comme les cellules entretenant les tumeurs, responsables de leur dissemination et des rechutes apres traitement. La decouverte des CSGs a conduit a un changement de paradigme dans le developpement des therapies anticancereuses, avec la necessite de cibler dans le traitement non seulement les cellules de la masse tumorale, mais aussi les CSGs. Un criblage differentiel de la chimiotheque Prestwick realise au laboratoire a permis d’identifier le bisacodyl comme une molecule presentant une cytotoxicite specifique sur les CSGs en quiescence.Cette these presente un travail sur la caracterisation des CSGs, la comprehension du mode d’action du bisacodyl, ainsi que l’evaluation de son potentiel therapeutique sur un modele 3D in intro et des modeles in vivo.

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