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Silencing of D4-GDI inhibits growth and invasive behavior in MDA-MB-231 cells by activation of Rac-dependent p38 and JNK signaling.

Abstract
The Rho GDP dissociation inhibitor D4-GDI is overexpressed in some human breast cancer cell lines (Zhang, Y., and Zhang, B. (2006) Cancer Res. 66, 5592-5598). Here, we show that silencing of D4-GDI by RNA interference abrogates tumor growth and lung metastasis of otherwise highly invasive MDA-MB-231 breast cancer cells. Under anchorage-independent culture conditions, D4-GDI-depleted cells undergo rapid apoptosis (anoikis), which is known to hinder metastasis. We also found that D4-GDI associates with Rac1 and Rac3 in breast cancer cells, but not with other Rho GTPases tested (Cdc42, RhoA, RhoC, and TC10). Silencing of D4-GDI results in constitutive Rac1 activation and translocation from the cytosol to cellular membrane compartments and in sustained activation of p38 and JNK kinases. Rac1 blockade inhibits p38/JNK kinase activities and the spontaneous anoikis of D4-GDI knockdown cells. These results suggest that D4-GDI regulates cell function by interacting primarily with Rac GTPases and may play an integral role in breast cancer tumorigenesis. D4-GDI could prove to be a potential new target for therapeutic intervention.
AuthorsYaqin Zhang, Leslie A Rivera Rosado, Sun Young Moon, Baolin Zhang
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 19 Pg. 12956-65 (May 08 2009) ISSN: 0021-9258 [Print] United States
PMID19269969 (Publication Type: Journal Article)
Chemical References
  • ARHGDIB protein, human
  • Guanine Nucleotide Dissociation Inhibitors
  • RAC1 protein, human
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • rho Guanine Nucleotide Dissociation Inhibitor beta
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • rac1 GTP-Binding Protein
Topics
  • Animals
  • Anoikis
  • Apoptosis
  • Blotting, Western
  • Breast Neoplasms (metabolism, pathology, prevention & control)
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Female
  • Gene Silencing (physiology)
  • Guanine Nucleotide Dissociation Inhibitors (genetics)
  • Humans
  • Immunoprecipitation
  • JNK Mitogen-Activated Protein Kinases (metabolism)
  • Lung Neoplasms (metabolism, prevention & control, secondary)
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • RNA, Small Interfering (pharmacology)
  • Signal Transduction
  • Tumor Suppressor Proteins (genetics)
  • p38 Mitogen-Activated Protein Kinases (metabolism)
  • rac1 GTP-Binding Protein (genetics, metabolism)
  • rho Guanine Nucleotide Dissociation Inhibitor beta
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors

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