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[Cancer Research 65, 6054-6062, July 15, 2005]
© 2005 American Association for Cancer Research

Molecular Biology, Pathobiology, and Genetics

Rho GDP Dissociation Inhibitor Protects Cancer Cells against Drug-Induced Apoptosis

Baolin Zhang1, Yaqin Zhang1, Marie-Claire Dagher2 and Emily Shacter1

1 Laboratory of Biochemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland and 2 Laboratoire de Biochimic et Biophysique des Systemes Integres, Commissariat al'Energie Atomique/Centre National de la Recherche Scientifique/l'Université Joseph Fourier, Grenoble, France

Requests for reprints: Baolin Zhang, 29 Lincoln Drive, Building 29A, Room 2B-24, Bethesda, MD 20892. Phone: 301-827-1784; Fax: 301-480-3256; E-mail: baolin.zhang{at}fda.gov.

Rho GDP dissociation inhibitor (RhoGDI) plays an essential role in control of a variety of cellular functions through interactions with Rho family GTPases, including Rac1, Cdc42, and RhoA. RhoGDI is frequently overexpressed in human tumors and chemoresistant cancer cell lines, raising the possibility that RhoGDI might play a role in the development of drug resistance in cancer cells. We found that overexpression of RhoGDI increased resistance of cancer cells (MDA-MB-231 human breast cancer cells and JLP-119 lymphoma cells) to the induction of apoptosis by two chemotherapeutic agents: etoposide and doxorubicin. Conversely, silencing of RhoGDI expression by DNA vector–mediated RNA interference (small interfering RNA) sensitized MDA-MB-231 cells to drug-induced apoptosis. Resistance to apoptosis was restored by reintroduction of RhoGDI protein expression. The mechanism for the antiapoptotic activity of RhoGDI may derive from its ability to inhibit caspase-mediated cleavage of Rac1 GTPase, which is required for maximal apoptosis to occur in response to cytotoxic drugs. Taken together, the data show that RhoGDI is an antiapoptotic molecule that mediates cellular resistance to these chemotherapy agents.




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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2005 by the American Association for Cancer Research.