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Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties
- Source :
- Oncogene
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
Abstract
- Advanced prostate adenocarcinomas enriched in stem-cell features, as well as variant androgen receptor (AR)-negative neuroendocrine (NE)/small-cell prostate cancers are difficult to treat, and account for up to 30% of prostate cancer-related deaths every year. While existing therapies for prostate cancer such as androgen deprivation therapy (ADT), destroy the bulk of the AR-positive cells within the tumor, eradicating this population eventually leads to castration-resistance, owing to the continued survival of AR-/lo stem-like cells. In this study, we identified a critical nexus between p38MAPK signaling, and the transcription factor Forkhead Box Protein C2 (FOXC2) known to promote cancer stem-cells and metastasis. We demonstrate that prostate cancer cells that are insensitive to ADT, as well as high-grade/NE prostate tumors, are characterized by elevated FOXC2, and that targeting FOXC2 using a well-tolerated p38 inhibitor restores epithelial attributes and ADT-sensitivity, and reduces the shedding of circulating tumor cells in vivo with significant shrinkage in the tumor mass. This study thus specifies a tangible mechanism to target the AR-/lo population of prostate cancer cells with stem-cell properties.
- Subjects :
- Male
0301 basic medicine
Cancer Research
Gene Expression
Epithelium
Metastasis
Androgen deprivation therapy
Mice
Prostate cancer
0302 clinical medicine
Recurrence
Prostate
Forkhead Transcription Factors
3. Good health
Prostate-specific antigen
Phenotype
medicine.anatomical_structure
Receptors, Androgen
030220 oncology & carcinogenesis
Benzamides
Androgens
Neoplastic Stem Cells
Original Article
PCA3
Epithelial-Mesenchymal Transition
MAP Kinase Signaling System
Biology
Models, Biological
03 medical and health sciences
Cell Line, Tumor
Nitriles
Phenylthiohydantoin
Genetics
medicine
Animals
Humans
Epithelial–mesenchymal transition
Molecular Biology
Prostatic Neoplasms
Zinc Finger E-box-Binding Homeobox 1
Cancer
Prostate-Specific Antigen
medicine.disease
Xenograft Model Antitumor Assays
Disease Models, Animal
030104 developmental biology
Drug Resistance, Neoplasm
Immunology
Cancer research
Neoplasm Grading
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 35
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....179e8eae0b34e393eef581b0df244c5a