A role for macroautophagy in protection against 4-hydroxytamoxifen–induced cell death and the development of antiestrogen resistance
| Autor: | Julia S. Samaddar, Darren D. Browning, Sudharsan Periyasamy Thandavan, Virgil T. Gaddy, Manish Shah, Jim Rawson, Marlena J. Smith, Patricia V. Schoenlein, Sylvia B. Smith, Jennifer Duplantier, John T. Barrett |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Autophagosome
Cancer Research Programmed cell death genetic structures Cell Survival Breast Neoplasms Biology Breast cancer Estrogen Receptor Modulators Cell Line Tumor Phagosomes Autophagy medicine Humans skin and connective tissue diseases Cancer medicine.disease Antiestrogen Caspase 9 Cell biology Tamoxifen Receptors Estrogen Oncology Drug Resistance Neoplasm Apoptosis Enzyme Induction Cancer research Female Drug Screening Assays Antitumor medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 7:2977-2987 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | This study identifies macroautophagy as a key mechanism of cell survival in estrogen receptor–positive (ER+) breast cancer cells undergoing treatment with 4-hydroxytamoxifen (4-OHT). This selective ER modifier is an active metabolite of tamoxifen commonly used for the treatment of breast cancer. Our study provides the following key findings: (a) only 20% to 25% of breast cancer cells treated with 4-OHT in vitro die via caspase-dependent cell death; more typically, the antiestrogen-treated ER+ breast cancer cells express increased levels of macroautophagy and are viable; (b) 4-OHT–induced cell death, but not 4-OHT–induced macroautophagy, can be blocked by the pan-caspase inhibitor z-VAD-fmk, providing strong evidence that these two outcomes of antiestrogen treatment are not linked in an obligatory manner; (c) 4-OHT–resistant cells selected from ER+ breast cancer cells show an increased ability to undergo antiestrogen-induced macroautophagy without induction of caspase-dependent cell death; and (d) 4-OHT, when used in combination with inhibitors of autophagosome function, induces robust, caspase-dependent apoptosis of ER+, 4-OHT–resistant breast cancer cells. To our knowledge, these studies provide the first evidence that macroautophagy plays a critical role in the development of antiestrogen resistance. We propose that targeting autophagosome function will improve the efficacy of hormonal treatment of ER+ breast cancer. [Mol Cancer Ther 2008;7(9):2977–87] |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|