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Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2007 Nov; Vol. 27 (21), pp. 7538-50. Date of Electronic Publication: 2007 Aug 20. - Publication Year :
- 2007
-
Abstract
- A hallmark of metastasis is organ specificity; however, little is known about the underlying signaling pathways responsible for the colonization and growth of tumor cells in target organs. Since tyrosine kinase receptor activation is frequently associated with prostate cancer progression, we have investigated the role of a common signaling intermediary, activated Ras, in prostate cancer metastasis. Three effector pathways downstream of Ras, Raf/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase, and Ral guanine nucleotide exchange factors (RalGEFs), were assayed for their ability to promote the metastasis of a tumorigenic, nonmetastatic human prostate cancer cell line, DU145. Oncogenic Ras promoted the metastasis of DU145 to multiple organs, including bone and brain. Activation of the Raf/ERK pathway stimulated metastatic colonization of the brain, while activation of the RalGEF pathway led to bone metastases, the most common organ site for prostate cancer metastasis. In addition, loss of RalA in the metastatic PC3 cell line inhibited bone metastasis but did not affect subcutaneous tumor growth. Loss of Ral appeared to suppress expansive growth of prostate cancer cells in bone, whereas homing and initial colonization were less affected. These data extend our understanding of the functional roles of the Ral pathway and begin to identify signaling pathways relevant for organ-specific metastasis.
- Subjects :
- Animals
Bone Neoplasms blood supply
Bone Neoplasms pathology
Brain Neoplasms blood supply
Brain Neoplasms pathology
Brain Neoplasms secondary
Cell Line, Tumor
Genes, ras
Humans
Male
Mice
Mutant Proteins metabolism
Organ Specificity
ras Proteins metabolism
Bone Neoplasms secondary
Prostatic Neoplasms pathology
Signal Transduction
ral GTP-Binding Proteins metabolism
ral Guanine Nucleotide Exchange Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 27
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 17709381
- Full Text :
- https://doi.org/10.1128/MCB.00955-07