Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy
| Autor: | Douglas C. Marchion, Kenneth T. Thurn, Elona Bicaku, Pamela N. Munster, Scott Thomas |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Cell signaling Indoles medicine.drug_class Poly (ADP-Ribose) Polymerase-1 Estrogen receptor Gene Expression Apoptosis Breast Neoplasms Biology Hydroxamic Acids Article chemistry.chemical_compound Panobinostat Cell Line Tumor medicine Autophagy Humans Vorinostat Estradiol Valproic Acid Histone deacetylase inhibitor Estrogen Receptor alpha Membrane Proteins Drug Synergism Cell biology Histone Deacetylase Inhibitors Tamoxifen Oncology chemistry Gene Knockdown Techniques Cancer research Beclin-1 Female Histone deacetylase Poly(ADP-ribose) Polymerases Apoptosis Regulatory Proteins Microtubule-Associated Proteins medicine.drug Signal Transduction |
| Popis: | 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 are 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. |
| Databáze: | OpenAIRE |
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