Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone.
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.
Yin
JuanJuan
J
Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, 37 Convent Dr., Rm. 1068, Bethesda, MD 20892, USA.
Pollock
Claire
C
Tracy
Kirsten
K
Chock
Monika
M
Martin
Philip
P
Oberst
Michael
M
Kelly
Kathleen
K
D000818:Animals; D001859:Bone Neoplasms / Q000098:blood supply / Q000473:pathology / Q000556:secondary*; D001932:Brain Neoplasms / Q000098:blood supply / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D011905:Genes, ras; D006801:Humans; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009928:Organ Specificity; D011471:Prostatic Neoplasms / Q000473:pathology*; D015398:Signal Transduction; D020725:ral GTP-Binding Proteins / Q000378:metabolism*; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D050505:Mutant Proteins; C483163:Ralb protein, human; D020726:ral Guanine Nucleotide Exchange Factor; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins; D018631:ras Proteins
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