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Identification and Characterization of Metastatic Factors by Gene Transfer into the Novel RIP-Tag; RIP-tva Murine Model
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RalBP1 is necessary for metastasis of human cancer cell lines

Zhong Wu1, Charles Owens, Nidhi Chandra

  • 1Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.

Neoplasia (New York, N.Y.)
|December 21, 2010
PubMed

Insights

RalA and Ral binding protein 1 (RalBP1) are crucial for human cancer cell migration and metastasis. RalBP1 is essential for metastasis in prostate and bladder cancers, independent of its direct interaction with RalA.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • RalA protein expression in human prostate cancer correlates with cell migration and bone metastasis.
  • The specific downstream targets of RalA that drive these metastatic processes are not fully understood.

Purpose of the Study:

  • To investigate the roles of RalA effectors, specifically Ral binding protein 1 (RalBP1), exocyst complex component 2 (Sec5), and phospholipase D1 (PLD1), in cancer cell migration and metastasis.
  • To determine if RalBP1 is essential for metastasis in cancers beyond prostate cancer.

Main Methods:

  • Small interfering RNA (siRNA) and short hairpin RNA (shRNA) were used to deplete RalA and its effectors in human prostate cancer (PC3) and bladder cancer (UMUC3) cell lines.
  • In vivo studies involved intracardiac inoculation of PC3 cells to assess bone metastasis and orthotopic implantation to evaluate tumor growth and spontaneous metastasis.
  • Experimental metastasis models were used to study lung colonization of UMUC3 cells.

Main Results:

  • Depletion of RalA and RalBP1 significantly inhibited prostate cancer cell migration and bone metastasis.
  • RalBP1 depletion reduced orthotopic tumor growth and spontaneous metastasis of PC3 cells.
  • RalBP1 depletion decreased lung colonization in a bladder cancer metastasis model, while having minimal impact on subcutaneous tumor growth.
  • Restoring RalA expression with wild-type or RalBP1-binding deficient mutants partially rescued the metastatic capacity of RalA-depleted cells, indicating RalA's function is not solely dependent on RalBP1 interaction.

Conclusions:

  • Ral binding protein 1 (RalBP1) is a critical mediator of human cancer cell metastasis in both prostate and bladder cancer.
  • RalA's role in promoting metastasis is not entirely dependent on its interaction with RalBP1.
  • RalBP1 represents a potential therapeutic target for inhibiting cancer metastasis.

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