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- Title
2-Methoxyestardiol and bortezomib/proteasome-inhibitor overcome dexamethasone-resistance in multiple myeloma cells by modulating Heat Shock Protein-27.
- Authors
Chauhan, D.; Li, G.; Auclair, D.; Hideshima, T.; Podar, K.; Mitsiades, N.; Mitsiades, C.; Chen, L. B.; Munshi, N.; Saxena, S.; Anderson, K. C.
- Abstract
Multiple myeloma (MM) remains fatal despite all available therapies. Initial treatment with conventional drugs such as, Dexamethasone (Dex) effectively induces MM cell death; however, prolonged drug exposures results in the development of chemoresistance. Our prior study demonstrated that 2-Methoxyestradiol (2ME2) induces apoptosis in multiple myeloma (MM) cells resistant to Dexamethasone (Dex). Here, we show the mechanism whereby 2ME2 overcomes Dex-resistance. The oligonucleotide array analysis demonstrates that Heat Shock Protein–27 (Hsp27) is upregulated in Dex-resistant, but not in Dex-sensitive MM cells. Proteomics analysis of Hsp27-immunocomplexes revealed the presence of actin in Dex-resistant, but not in Dex-sensitive cells. Biochemical interaction between Hsp27 and actin was examined by co-immunoprecipitation with anti-Hsp27 or actin Abs. Far western blot analysis using GST-Hsp27 fusion protein showed a direct association with actin both in vitro and in vivo. Importantly, 2ME2- or Bortezomib/Proteasome inhibitor (PS-341)-induced apoptosis in Dex-resistant MM cell lines and MM patient cells is associated with disruption of the Hsp27-actin complexes. Finally, blockade of Hsp27 by anti-sense strategy enhanced anti-MM activity of both 2ME2 and PS-341. These findings provide the clinical application of novel therapeutics targeting Hsp27 to improve patient outcome in MM.
- Subjects
CELL death; ACTOMYOSIN; PLASMACYTOMA; MULTIPLE myeloma; APOPTOSIS; THERAPEUTICS
- Publication
Apoptosis, 2004, Vol 9, Issue 2, p149
- ISSN
1360-8185
- Publication type
Article
- DOI
10.1023/B:APPT.0000018797.66067.6c