Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy
Identifieur interne : 001584 ( Main/Exploration ); précédent : 001583; suivant : 001585Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy
Auteurs : Scott Thomas [États-Unis] ; Kenneth T. Thurn [États-Unis] ; Elona Biçaku [États-Unis] ; Douglas C. Marchion [États-Unis] ; Pamela N. Münster [États-Unis]Source :
- Breast Cancer Research and Treatment [ 0167-6806 ] ; 2011-11-01.
English descriptors
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Abstract
Abstract: Modulation of estrogen signaling is one of the most successful modalities for the treatment of estrogen receptor (ER)-positive breast cancer, yet de novo and acquired resistance are frequent. Recent data suggests that the induction of autophagy may play a considerable role in promoting tumor cell survival and resistance to anti-estrogen therapy. Hence, bypassing autophagy may offer a novel strategy to enhance the anti-tumor efficacy of anti-estrogens. Histone deacetylases (HDAC) are involved in the regulation of steroid hormone receptor mediated cell signaling and their inhibition potentiates the anti-tumor effects of anti-estrogens. However, the mechanism underlying this anti-tumor activity is poorly understood. In this report, we show that the addition of an HDAC inhibitor redirects the response of ER-positive breast cancer cells when treated with tamoxifen from growth arrest to apoptotic cell death. This redirection requires functional ER signaling and is mediated by a depletion of Bcl-2 and an induction of Bax and Bak, manifesting in cytochrome C release and PARP cleavage. With combined treatment, a subpopulation of cells is refractory to apoptosis and exhibit a strong induction of autophagy. Inhibition of autophagy in these cells, using siRNA directed against Beclin-1 or treatment with chloroquine, further promotes the induction of apoptosis. Thus, supporting prior reports that autophagy acts as a survival mechanism, our findings demonstrate that HDAC and autophagy inhibition directs autophagy-protected cells into apoptotic cell death, which may impair development of tamoxifen resistance.
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DOI: 10.1007/s10549-011-1364-y
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Recent data suggests that the induction of autophagy may play a considerable role in promoting tumor cell survival and resistance to anti-estrogen therapy. Hence, bypassing autophagy may offer a novel strategy to enhance the anti-tumor efficacy of anti-estrogens. Histone deacetylases (HDAC) are involved in the regulation of steroid hormone receptor mediated cell signaling and their inhibition potentiates the anti-tumor effects of anti-estrogens. However, the mechanism underlying this anti-tumor activity is poorly understood. In this report, we show that the addition of an HDAC inhibitor redirects the response of ER-positive breast cancer cells when treated with tamoxifen from growth arrest to apoptotic cell death. This redirection requires functional ER signaling and is mediated by a depletion of Bcl-2 and an induction of Bax and Bak, manifesting in cytochrome C release and PARP cleavage. With combined treatment, a subpopulation of cells is refractory to apoptosis and exhibit a strong induction of autophagy. Inhibition of autophagy in these cells, using siRNA directed against Beclin-1 or treatment with chloroquine, further promotes the induction of apoptosis. Thus, supporting prior reports that autophagy acts as a survival mechanism, our findings demonstrate that HDAC and autophagy inhibition directs autophagy-protected cells into apoptotic cell death, which may impair development of tamoxifen resistance.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li><li>Floride</li></region></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Thomas, Scott" sort="Thomas, Scott" uniqKey="Thomas S" first="Scott" last="Thomas">Scott Thomas</name></region><name sortKey="Bicaku, Elona" sort="Bicaku, Elona" uniqKey="Bicaku E" first="Elona" last="Biçaku">Elona Biçaku</name><name sortKey="Marchion, Douglas C" sort="Marchion, Douglas C" uniqKey="Marchion D" first="Douglas C." last="Marchion">Douglas C. Marchion</name><name sortKey="Munster, Pamela N" sort="Munster, Pamela N" uniqKey="Munster P" first="Pamela N." last="Münster">Pamela N. 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