Back to Search
Start Over
Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of bim
- Source :
- Oncogene
- Publication Year :
- 2009
-
Abstract
- Notch signaling is a highly conserved pathway important for normal embryonic development and cancer. We previously demonstrated a role for Notch3 in lung cancer pathogenesis. Notch3 inhibition resulted in tumor apoptosis and growth suppression. In vitro, these effects were enhanced when the epidermal growth factor receptor (EGFR) pathway was also inhibited, suggesting significant cross-talk between the two pathways. How Notch3 and epidermal growth factor receptor-mitogen-activated protein kinase (EGFR-MAPK) pathways cooperate in modulating apoptosis is not yet known. In this study, we provide evidence that Notch3 regulates Bim, a BH-3-only protein, via MAPK signaling. Furthermore, loss of Bim expression prevents tumor apoptosis induced by Notch3 inhibition. Using gamma-secretase inhibitor and erlotinib in a xenograft model, Bim induction and tumor inhibition were observed to be enhanced compared with either agent alone, consistent with our previous observation of significant synergism between Notch and EGFR-ras-MAPK signaling. Thus, our data support the hypothesis that Notch3 not only has a crucial role in lung cancer through regulating apoptosis, but also cooperates with the EGFR-MAPK pathway in modulating Bim.
- Subjects :
- Cancer Research
medicine.medical_specialty
MAP Kinase Signaling System
Notch signaling pathway
Mice, Nude
Apoptosis
medicine.disease_cause
Article
03 medical and health sciences
Erlotinib Hydrochloride
Mice
0302 clinical medicine
Epidermal growth factor
Internal medicine
Cell Line, Tumor
Neoplasms
Proto-Oncogene Proteins
Genetics
medicine
Animals
Bim
Epidermal growth factor receptor
RNA, Small Interfering
Protein kinase A
Molecular Biology
Protein Kinase Inhibitors
Receptor, Notch3
030304 developmental biology
0303 health sciences
biology
Bcl-2-Like Protein 11
Receptors, Notch
Lung Cancer
Notch3
Membrane Proteins
Xenograft Model Antitumor Assays
ErbB Receptors
Endocrinology
030220 oncology & carcinogenesis
Cancer research
biology.protein
Quinazolines
Female
Erlotinib
Carcinogenesis
Apoptosis Regulatory Proteins
medicine.drug
Subjects
Details
- ISSN :
- 14765594
- Volume :
- 29
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....ba040ef4c67c09d753314596f84c70e4