Samenvatting
It is well known that hypoxia is associated with increased metastatic potential and treatment-resistance in solid tumor, however, the oxygen level in bone marrow (BM) and the role of hypoxia in the pathogenesis of hematological malignancies such as multiple myeloma (MM) is still unclear. By staining the exogenous and endogenous hypoxia
markers pimonidazole and HIF-1a in the bone marrow of naive and 5T33MM mice, we demonstrated that MM cells exist in a hypoxic niche (Jinsong Hu, et al. 51st ASH annual meeting, http://ash.confex.com/ash/2009/webprogram/Paper19995.html). In this study, we further investigated the protective role of Bcl-2 and Bcl-xL in hypoxia-induced MM cell death. We found that hypoxia (1% O2 and 0% O2) can increase the expression of Bcl-2 and Bcl-xL at both mRNA and protein levels by qRT-PCR and Western blot.
Moreover, stabilization of HIF1a enhances Bcl-2/Bcl-xL expression in normoxic condition. In contrast, inhibition of the accumulation of HIF1a decreases Bcl-2/Bcl-xL expression in hypoxic condition. Antagonizing Bcl-2 and Bcl-xL with ABT-737 (which is a BH3 mimetic small-molecule inhibitor that binds with high affinity to Bcl-2 and Bcl-xL) overcomes Bcl-2/Bcl-xL mediated MM cell apoptotic resistance to hypoxic stress, by increasing the expression of cleaved proapoptotic proteins caspase-3, 9 and PARP. ABT-737 in combination with HIF1a inhibitor can synergistically induce MM cell apoptosis in hypoxic condition. In conclusion, (1) Bcl-2 and Bcl-xL are target genes of HIF1a. (2) MM cells
protect themselves from hypoxia-induced apoptosis by up-regulating Bcl-2 and Bcl-xL expression.
markers pimonidazole and HIF-1a in the bone marrow of naive and 5T33MM mice, we demonstrated that MM cells exist in a hypoxic niche (Jinsong Hu, et al. 51st ASH annual meeting, http://ash.confex.com/ash/2009/webprogram/Paper19995.html). In this study, we further investigated the protective role of Bcl-2 and Bcl-xL in hypoxia-induced MM cell death. We found that hypoxia (1% O2 and 0% O2) can increase the expression of Bcl-2 and Bcl-xL at both mRNA and protein levels by qRT-PCR and Western blot.
Moreover, stabilization of HIF1a enhances Bcl-2/Bcl-xL expression in normoxic condition. In contrast, inhibition of the accumulation of HIF1a decreases Bcl-2/Bcl-xL expression in hypoxic condition. Antagonizing Bcl-2 and Bcl-xL with ABT-737 (which is a BH3 mimetic small-molecule inhibitor that binds with high affinity to Bcl-2 and Bcl-xL) overcomes Bcl-2/Bcl-xL mediated MM cell apoptotic resistance to hypoxic stress, by increasing the expression of cleaved proapoptotic proteins caspase-3, 9 and PARP. ABT-737 in combination with HIF1a inhibitor can synergistically induce MM cell apoptosis in hypoxic condition. In conclusion, (1) Bcl-2 and Bcl-xL are target genes of HIF1a. (2) MM cells
protect themselves from hypoxia-induced apoptosis by up-regulating Bcl-2 and Bcl-xL expression.
| Originele taal-2 | English |
|---|---|
| Titel | 25th General Meeting of the Belgian Hematological Society - Abstract Posters Clinical Hematology p 39 |
| Uitgeverij | Belgian Hematological Society |
| Status | Published - 29 jan 2010 |