MCB Accepts, published online ahead of print on 20 August 2007

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Mol. Cell. Biol. doi:10.1128/MCB.00955-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Activation of the RalGEF/Ral Pathway Promotes Prostate Cancer Metastasis to Bone

JuanJuan Yin, Claire Pollock, Kirsten Tracy, Monika Chock, Philip Martin, Michael Oberst, and Kathleen Kelly^*

Cell and Cancer Biology Branch, Center for Cancer Research, NCI, 37 Convent Drive, Room 1068, Bethesda, MD 20892

^* To whom correspondence should be addressed. Email: kellyka{at}mail.nih.gov.

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. As 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/ERK, PI3-kinase, and Ral guanine nucleotide exchange factors (RalGEFs), were assayed for their ability to promote metastasis of a tumorigenic, non-metastatic human prostate cancer cell line, DU145. Oncogenic Ras promoted 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.

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