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Identification of markers that functionally define a quiescent multiple myeloma cell sub-population surviving bortezomib treatment.
- Source :
- BMC Cancer; 2015, Vol. 15 Issue 1, p1-11, 11p, 1 Chart, 4 Graphs
- Publication Year :
- 2015
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- MULTIPLE myeloma
CANCER cells
BORTEZOMIB
TUMOR markers
AZACITIDINE
Subjects
Details
- Language :
- English
- ISSN :
- 14712407
- Volume :
- 15
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- BMC Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 108306718
- Full Text :
- https://doi.org/10.1186/s12885-015-1460-1