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c-Src modulates estrogen-induced stress and apoptosis in estrogen-deprived breast cancer cells
- Publication Year :
- 2013
-
Abstract
- The emergence of anti-estrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease. Identifying factors that convey cell survival in this setting may guide improvements in treatment. Estrogen (E2) can induce apoptosis in breast cancer cells that have been selected for survival after E2 deprivation for long periods (MCF-7:5C cells), but the mechanisms underlying E2-induced stress in this setting have not been elucidated. Here, we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor (ER, ESR1) in its activation of stress responses induced by E2 in MCF-7:5C cells. E2 elevated phosphorylation of c-Src, which was blocked by 4-hydroxytamoxifen (4-OHT), suggesting that E2 activated c-Src through the ER. We found that E2 activated the sensors of the unfolded protein response (UPR), IRE1α (ERN1) and PERK kinase (EIF2AK3), the latter of which phosphorylates eukaryotic translation initiation factor-2α (eIF2α). E2 also dramatically increased reactive oxygen species production and upregulated expression of heme oxygenase HO-1 (HMOX1), an indicator of oxidative stress, along with the central energy sensor kinase AMPK (PRKAA2). Pharmacologic or RNA interference–mediated inhibition of c-Src abolished the phosphorylation of eIF2α and AMPK, blocked E2-induced ROS production, and inhibited E2-induced apoptosis. Together, our results establish that c-Src kinase mediates stresses generated by E2 in long-term E2-deprived cells that trigger apoptosis. This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer. Cancer Res; 73(14); 4510–20. ©2013 AACR.
- Subjects :
- Cancer Research
Eukaryotic Initiation Factor-2
Estrogen receptor
Apoptosis
Breast Neoplasms
AMP-Activated Protein Kinases
Protein Serine-Threonine Kinases
Endoplasmic Reticulum
Article
CSK Tyrosine-Protein Kinase
eIF-2 Kinase
Cell Line, Tumor
Endoribonucleases
Humans
EIF2AK3
Phosphorylation
EIF-2 kinase
biology
Kinase
AMPK
Estrogens
Cell biology
Oxidative Stress
src-Family Kinases
Oncology
Receptors, Estrogen
biology.protein
Cancer research
Unfolded protein response
MCF-7 Cells
Unfolded Protein Response
Female
Reactive Oxygen Species
Estrogen receptor alpha
Heme Oxygenase-1
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....b0946d829299472421b4cd63aac0bbd8