Rho GDP dissociation inhibitor protects cancer cells against drug-induced apoptosis.
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 chemo-resistant 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 anti-apoptotic 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 anti-apoptotic molecule that mediates cellular resistance to these chemotherapy agents.
Zhang
Baolin
B
Laboratory of Biochemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA. baolin.zhang@fda.gov
Zhang
Yaqin
Y
Dagher
Marie-Claire
MC
Shacter
Emily
E
D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008969:Molecular Sequence Data; D009154:Mutation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
C569638:ARHGDIA protein, human; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D020730:Guanine Nucleotide Dissociation Inhibitors; D034741:RNA, Small Interfering; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D005047:Etoposide; D004317:Doxorubicin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D020830:rac1 GTP-Binding Protein