Tamoxifen and tamoxifen ethyl bromide induce apoptosis in acutely damaged mammary epithelial cells through modulation of AKT activity
| Autor: | Gregory R. Bean, Michelle L. Bowie, Paul B. Rosenberg, Michelle M. Troch, Brooke Ratliff, Eric C. Dietze, Victoria L. Seewaldt, Joshua B Heffner |
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| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
medicine.medical_specialty Caspase 3 Apoptosis Biology Mitochondrion Protein Serine-Threonine Kinases Cell Line Membrane Potentials Internal medicine Proto-Oncogene Proteins Genetics medicine Humans Breast Phosphorylation Molecular Biology Protein kinase B Estradiol Epithelial Cells Caspase 9 Mitochondria body regions Tamoxifen Endocrinology Cell culture Caspases Cancer research Female Signal transduction Proto-Oncogene Proteins c-akt medicine.drug Signal Transduction |
| Zdroj: | Oncogene. 23(21) |
| ISSN: | 0950-9232 |
| Popis: | Normal human mammary epithelial cells (HMECs), unlike estrogen receptor-positive (ER+) breast cancers, typically express low nuclear levels of ER (ER-'poor'). We previously demonstrated that 1.0 microM tamoxifen (Tam) induced apoptosis in ER-'poor' HMECs acutely transduced with human papillomavirus-16 E6 (HMEC-E6) through a rapid mitochondrial signaling pathway. Here, we show that plasma membrane-associated E2-binding sites initiate the rapid apoptotic effects of Tam in HMEC-E6 cells through modulation of AKT activity. At equimolar concentrations, Tam and tamoxifen ethyl bromide (QTam), a membrane impermeant analog of Tam, rapidly induced apoptosis in HMEC-E6 cells associated with an even more rapid decrease in phosphorylation of AKT at serine-473. Treatment of HMEC-E6 cells with 1.0 microM QTam resulted in a 50% decrease in mitochondrial transmembrane potential, sequential activation of caspase-9 and -3, and a 90% decrease in AKT Ser-473 phosphorylation. The effects of both Tam and QTam were blocked by expression of constitutively active AKT (myristoylated AKT or AKT-Thr308Asp/Ser473Asp). These data indicate that Tam and QTam induce apoptosis in HMEC-E6 cells through a plasma membrane-activated AKT-signaling pathway that results in (1) decreased AKT phosphorylation at Ser-473, (2) mitochondrial membrane depolarization, and (3) activated caspase-9 and -3. |
| Databáze: | OpenAIRE |
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