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Propagation of human prostate cancer stem-like cells occurs through EGFR-mediated ERK activation
- Source :
- PLoS ONE, PLoS ONE, Vol 8, Iss 4, p e61716 (2013)
- Publication Year :
- 2012
-
Abstract
- Prostate cancer stem-like cells (PCSCs) are being intensely investigated largely owing to their contributions towards prostate tumorigenesis, however, our understanding of PCSC biology, including their critical pathways, remains incompletely understood. While epidermal growth factor (EGF) is widely used in maintaining PCSC cells in vitro, the importance of EGF-dependent signaling and its downstream pathways in PCSC self-renewal are not well characterized. By investigating DU145 sphere cells, a population of prostate cancer cells with stem-like properties, we report here that epidermal growth factor receptor (EGFR) signaling plays a critical role in the propagation of DU145 PCSCs. Activation of EGFR signaling via addition of EGF and ectopic expression of a constitutively-active EGFR mutant (EGFRvIII) increased sphere formation. Conversely, inhibition of EGFR signaling by using EGFR inhibitors (AG1478 and PD168393) and knockdown of EGFR significantly inhibited PCSC self-renewal. Consistent with the MEK-ERK pathway being a major target of EGFR signaling, activation of the MEK-ERK pathway contributed to EGFR-facilitated PCSC propagation. Modulation of EGFR signaling affected extracellular signal-related kinase (ERK) activation. Inhibition of ERK activation through multiple approaches, including treatment with the MEK inhibitor U0126, ectopic expression of dominant-negative MEK1(K97M), and knockdown of either ERK1 or ERK2 resulted in a robust reduction in PCSC propagation. Collectively, the present study provides evidence that EGFR signaling promotes PCSC self-renewal, in part, by activating the MEK-ERK pathway.
- Subjects :
- MAPK/ERK pathway
Male
lcsh:Medicine
Signal transduction
ERK signaling cascade
0302 clinical medicine
Molecular cell biology
Epidermal growth factor
Signaling in Cellular Processes
Epidermal growth factor receptor
lcsh:Science
Extracellular Signal-Regulated MAP Kinases
EGFR inhibitors
0303 health sciences
education.field_of_study
Multidisciplinary
biology
MEK inhibitor
Stem Cells
Prostate Cancer
Signaling cascades
Signaling in Selected Disciplines
3. Good health
Cell biology
ErbB Receptors
Oncology
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Neoplastic Stem Cells
Medicine
Cellular Types
Research Article
MAPK signaling cascades
Population
03 medical and health sciences
DU145
Cell Line, Tumor
Spheroids, Cellular
Humans
education
Biology
030304 developmental biology
Cell Proliferation
Mitogen-Activated Protein Kinase Kinases
Oncogenic Signaling
lcsh:R
Prostatic Neoplasms
Cancers and Neoplasms
Enzyme Activation
Genitourinary Tract Tumors
HEK293 Cells
Cancer research
biology.protein
lcsh:Q
Mitogens
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 8
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....18c1eeaefaf536654002144731fa8056