RalBP1 is necessary for metastasis of human cancer cell lines
Open accessAbstract
RalA expression in human prostate cancer is associated with cell migration and is necessary for bone metastasis. However, the downstream effectors of RalA that mediate these functions remain unclear. Here we examined cell migration after small interfering RNA-mediated depletion of Ral effectors Ral binding protein 1 (RalBP1/RLIP), exocyst complex component 2 (Sec5), and phospholipase D1 (PLD1) and found that RalBP1 and RalA depletion inhibited cell migration to a similar extent. Stable lentivirus short hairpin interfering RNA-mediated depletion of RalA and RalBP1 in PC3 human prostate cancer cells inhibited bone metastasis after intracardiac inoculation. Depletion of RalBP1 diminished orthotopic tumor growth of PC3 cells and inhibited spontaneous metastasis from this site. Interestingly, the expression of wild-type or RalA mutants deficient in RalBP1 binding was effective at rescuing the reduced metastatic capacity of RalA-depleted PC3 cells, suggesting that RalA depletion does not reduce this solely by diminished interaction with RalBP1. To determine whether the role of RalBP1 in metastasis is relevant beyond prostate cancer, we studied the requirement of RalBP1 expression in an experimental metastasis model of human bladder cancer, a tumor type with high RalBP1 expression. Depletion of RalBP1 in UMUC3 cells resulted in decreased lung colonization while having a minimal effect on subcutaneous tumor growth. Our studies are the first to suggest that the expression of RalBP1 is necessary for human cancer cell metastasis. Furthermore, we show that the requirement for RalA expression for manifestation of this phenotype is not entirely dependent on a RalA-RalBP1 interaction.
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Rlip is important for metastasis.
“Rlip, as might be expected for a downstream Ras effector, has been found to be important for metastasis [102].”
From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [102]
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Regulated RalBP1 Binding to RalA and PSD-95 Controls AMPA Receptor Endocytosis and LTD
Han, K., Kim, M.-H., Seeburg, D., Seo, J., Verpelli, C., Han, S., Chung, H. S., Ko, J., Lee, H. W., Kim, K., et al. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000187 · Cited by 71 · see citing works
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Research works printed but not linked: 3
- Smith SC, Oxford G, Baras AS, Owens C, Havaleshko D, Brautigan DL, Safo MK, and Theodorescu D (2007). Expression of ral GTPases, their effectors, and activators in human bladder cancer. Clin Cancer Res 13, 3803-3813.
- Oxford G, Owens CR, Titus BJ, Foreman TL, Herlevsen MC, Smith SC, and Theodorescu D (2005). RalA and RalB: antagonistic relatives in cancer cell migration. Cancer Res 65, 7111-7120.
- Gildea JJ, Seraj MJ, Oxford G, Harding MA, Hampton GM, Moskaluk CA, Frierson HF, Conaway MR, and Theodorescu D (2002). RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. Cancer Res 62, 6418-6423.
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CD24 Is an Effector of HIF-1–Driven Primary Tumor Growth and Metastasis
Thomas, S., Harding, M. A., Smith, S. C., Overdevest, J. B., Nitz, M. D., Frierson, H. F., Tomlins, S. A., Kristiansen, G., & Theodorescu, D. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3666 · Cited by 128 · see citing works
Self-citationRal signaling pathway in health and cancer
Moghadam, A. R., Patrad, E., Tafsiri, E., Peng, W., Fangman, B., Pluard, T. J., Accurso, A., Salacz, M., Shah, K., Ricke, B., et al. (2017) · Cancer Medicine · doi:10.1002/cam4.1105 · Cited by 58 · see citing works
Differential involvement of RalA and RalB in colorectal cancer
Martin, T. D., & Der, C. J. (2012) · Small GTPases · doi:10.4161/sgtp.19571 · Cited by 36 · see citing works
Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?
Hindle, A., Singh, S. P., Pradeepkiran, J. A., Bose, C., Vijayan, M., Kshirsagar, S., Sawant, N. A., & Reddy, P. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116098 · Cited by 14 · see citing works
- Authors
- Wu, Z., Owens, C., Chandra, N., Popovic, K., Conaway, M., & Theodorescu, D.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Theodorescu, Dan
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 12
- Issue
- 12
- Pages
- 1003-1012
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC3003135
- OpenAlex
- W1934430972
- Cited by
- 70
- References
- 1
- Citations by year
- 2026: 2 · 2025: 3 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 7 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 5 · 2014: 2 · 2013: 3 · 2012: 10
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (CA104106)
- National Cancer Institute (P01CA104106, R01CA075115, CA 104106)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- RALBP1, RalA, metastasis, prostate cancer, bone metastasis, bladder cancer, cell migration, exocyst complex, Sec5, phospholipase D1, lung colonization, orthotopic tumor growth
- MeSH terms
- Animals, Urinary Bladder Neoplasms, Bone Neoplasms, Cell Movement, Humans, Lung Neoplasms, Male, Mice, Nude, Neoplasm Metastasis, Neoplasm Transplantation, Phospholipase D, Prostatic Neoplasms, Transplantation, Heterologous, Blotting, Western, ATP-Binding Cassette Transporters, Reverse Transcriptase Polymerase Chain Reaction, GTPase-Activating Proteins, ral GTP-Binding Proteins, Vesicular Transport Proteins, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, Mice, Inverted Repeat Sequences
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