期刊
CLINICAL CANCER RESEARCH
卷 13, 期 16, 页码 4882-4890出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-06-3093
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Purpose: The molecular chaperone heat shock protein (hsp)-90 maintains estrogen receptor (ER)-alpha in an active conformation, allowing it to bind 17 beta-estradiol (E-2) and transactivate genes, including progesterone receptor (PR)-p and the class IIB histone cleacetylase HDAC6. By inhibiting HDAC6, the hydroxamic acid analogue pan-HDAC inhibitors (HA-HDI; e.g., LAQ824, LBH589, and vorinostat) induce hyperacetylation of the HDAC6 substrates alpha-tubulin and hsp90. Hyperacetylation of hsp90 inhibits its chaperone function, thereby depleting hsp90 client proteins. Here, we determined the effect of HA-HDIs on the levels and activity of ER alpha as well as on the survival of ER alpha-expressing, estrogen- responsive human breast cancer MCF-7 and BT-474 cells. Experimental Design: Following exposure to HA-HDIs, hsp90 binding, polyubiquitylation levels, and transcriptional activity of ERa, as well as apoptosis and loss of survival, were determined in MCF-7 and BT-474 cells. Results: Treatment with HA-HDI induced hsp90 hype ra cetylatio n, decreased its binding to ERU, and increased polyubiquitylation and depletion of ER alpha levels. HA-HDI treatment abrogated E-2-induced estrogen response element- luciferase expression and attenuated PRO and HDAC6 levels. Exposure to HA-HDI also depleted p-Akt, Akt, c-Raf, and phospho-extracellular signal regulated kinase-1/2 levels, inhibited growth, and sensitized ER alpha-positive breast cancer cells to tamoxifen. Conclusions: These findings show that treatment with HA-HDI abrogates ERU levels and activity and could sensitize ERa-positive breast cancers to E-2 depletion or ER alpha antagonists.
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