Palbociclib Effectively Halts Proliferation but Fails to Induce Senescence in Patient-Derived Glioma Stem Cells
| Autor: | María Elida Scassa, Damián Darío Fernandez-Espinosa, Guillermo Agustín Videla-Richardson, Mariela C. Marazita, Gustavo Sevlever, Luciana Isaja, Leonardo Romorini, Olivia Morris-Hanon |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell cycle checkpoint Pyridines Neuroscience (miscellaneous) Apoptosis Palbociclib Biology Piperazines 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cyclin-dependent kinase Glioma Cell Line Tumor medicine Roscovitine Humans Cellular Senescence Cell Proliferation Brain Neoplasms Cancer Cyclin-Dependent Kinase 4 Cell Cycle Checkpoints Cyclin-Dependent Kinase 6 Fibroblasts medicine.disease 030104 developmental biology Phenotype Neurology Tumor progression Cancer research biology.protein Neoplastic Stem Cells Cyclin-dependent kinase 6 Stem cell 030217 neurology & neurosurgery |
| Zdroj: | Molecular neurobiology. 56(11) |
| ISSN: | 1559-1182 |
| Popis: | Glioblastoma multiforme is the most aggressive primary brain tumor. Current knowledge suggests that the growth and recurrence of these tumors are due in part to the therapy-resistant glioma stem cell subpopulation, which possesses the ability for self-renewal and proliferation, driving tumor progression. In many cancers, the p16INK4a-CDK4/6-pRb pathway is disrupted in favor of cell cycle progression. In particular, the frequent deregulation of CDK4/6 in cancer positions these kinases as promising targets. Palbociclib, a potent and selective CDK4/6 inhibitor, has been approved by the FDA as a first-line treatment of advanced breast cancer and there is currently interest in evaluating its effect on other cancer types. Palbociclib has been reported to be efficient, not only at halting proliferation, but also at inducing senescence in different tumor types. In this study, we evaluated the effect of this inhibitor on four patient-derived glioma stem cell-enriched cell lines. We found that Palbociclib rapidly and effectively inhibits proliferation without affecting cell viability. We also established that in these cell lines CDK6 is the key interphase CDK for controlling cell cycle progression. Prolonged exposure to Palbociclib induced a senescent-like phenotype characterized by flattened morphology, cell cycle arrest, increased β-galactosidase activity and induction of other senescent-associated markers. However, we found that after Palbociclib removal cell lines resumed normal proliferation, which implies they conserved their replicative potential. As a whole, our results indicate that in patient-derived glioma stem cell-enriched cell lines, Palbociclib induces a senescent-like quiescence rather than true senescence. |
| Databáze: | OpenAIRE |
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