Identification of markers that functionally define a quiescent multiple myeloma cell sub-population surviving bortezomib treatment
| Autor: | Ajai Chari, Julio A. Aguirre-Ghiso, Noa Biran, Adrienne W. Paton, Denis M. Schewe, Alfred Adomako, Kateri A. Moore, Veronica Calvo, Keren Osman, James C. Paton |
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| Jazyk: | angličtina |
| Předmět: |
Adult
Male Cancer Research Cell Survival Cell Population Apoptosis Bortezomib Mice Downregulation and upregulation In vivo Genetics Medicine Animals Humans education Endoplasmic Reticulum Chaperone BiP Heat-Shock Proteins Aged education.field_of_study business.industry Cyclin-Dependent Kinase 6 Middle Aged Xenograft Model Antitumor Assays In vitro 3. Good health Gene Expression Regulation Neoplastic medicine.anatomical_structure p21-Activated Kinases Oncology Cancer research Azacitidine Female Stem cell Neoplasm Recurrence Local business Multiple Myeloma medicine.drug Research Article |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| DOI: | 10.1186/s12885-015-1460-1 |
| Popis: | Background The mechanisms allowing residual multiple myeloma (MM) cells to persist after bortezomib (Bz) treatment remain unclear. We hypothesized that studying the biology of bortezomib-surviving cells may reveal markers to identify these cells and survival signals to target and kill residual MM cells. Methods We used H2B-GFP label retention, biochemical tools and in vitro and in vivo experiments to characterize growth arrest and the unfolded protein responses in quiescent Bz-surviving cells. We also tested the effect of a demethylating agent, 5-Azacytidine, on Bz-induced quiescence and whether inhibiting the chaperone GRP78/BiP (henceforth GRP78) with a specific toxin induced apoptosis in Bz-surviving cells. Finally, we used MM patient samples to test whether GRP78 levels might associate with disease progression. Statistical analysis employed t-test and Mann-Whitney tests at a 95% confidence. Results We report that Bz-surviving MM cells in vitro and in vivo enter quiescence characterized by p21CIP1 upregulation. Bz-surviving MM cells also downregulated CDK6, Ki67 and P-Rb. H2B-GFP label retention showed that Bz-surviving MM cells are either slow-cycling or deeply quiescent. The Bz-induced quiescence was stabilized by low dose (500nM) of 5-azacytidine (Aza) pre-treatment, which also potentiated the initial Bz-induced apoptosis. We also found that expression of GRP78, an unfolded protein response (UPR) survival factor, persisted in MM quiescent cells. Importantly, GRP78 downregulation using a specific SubAB bacterial toxin killed Bz-surviving MM cells. Finally, quantification of Grp78high/CD138+ MM cells from patients suggested that high levels correlated with progressive disease. Conclusions We conclude that Bz-surviving MM cells display a GRP78HIGH/p21HIGH/CDK6LOW/P-RbLOW profile, and these markers may identify quiescent MM cells capable of fueling recurrences. We further conclude that Aza + Bz treatment of MM may represent a novel strategy to delay recurrences by enhancing Bz-induced apoptosis and quiescence stability. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1460-1) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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