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Molecular and Cellular Biology, November 2007, p. 7538-7550, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00955-07
Copyright © 2007, American Society for Microbiology. 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, National Cancer Institute, 37 Convent Drive, Room 1068, Bethesda, Maryland 20892

Received 30 May 2007/ Returned for modification 19 July 2007/ Accepted 13 August 2007

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.

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* Corresponding author. Mailing address: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, 37 Convent Dr., Rm. 1068, Bethesda, MD 20892. Phone: (301) 435-4651. Fax: (301) 435-4655. E-mail: kellyka{at}mail.nih.gov

Published ahead of print on 20 August 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

J.Y. and C.P. contributed equally to this study.

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Molecular and Cellular Biology, November 2007, p. 7538-7550, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00955-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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