Geranylgeranyltransferase I inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice.

Abstract

Treatment of H-Ras transgenic mice with the geranylgeranyltransferase I (GGTase I) inhibitor GGTI-2154 results not only in halting the growth of aggressive breast tumors but actually in inducing the regression (54 +/- 3%) of all 19 tumors analyzed. The farnesyltransferase (FTase) inhibitor FTI-2148 induced an average of 87 +/- 3% regression in the 13 tumors analyzed. GGTase I, but not FTase, is inhibited in breast tumors after treatment with GGTI-2154, whereas in tumors from mice treated with FTI-2148, only FTase is inhibited. The processing of the geranylgeranylated proteins RhoA, Rap1, and R-Ras, but not the farnesylated proteins H-Ras and HDJ-2, is inhibited in tumors obtained from mice treated with GGTI-2154. GGTI-2154 and FTI-2148 suppress constitutively activated phospho-Erk1/2 and phospho-Akt, induce apoptosis, and induce differentiation toward ductolobular breast epithelium. The data demonstrate that geranylgeranylated proteins are critical in H-Ras oncogenesis in vivo and give strong support for GGTase I as a target for anticancer drug discovery.

• Authors: Jiazhi Sun, Junko Ohkanda, Domenico Coppola, Hang Yin, Mohit Kothare, Brian Busciglio, Andrew D Hamilton, Saïd M Sebti
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 24 Pg. 8922-9 (Dec 15 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14695209 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carrier Proteins
• DNAJA1 protein, human
• Enzyme Inhibitors
• GGTI-2154
• HSP40 Heat-Shock Proteins
• Heat-Shock Proteins
• Imidazoles
• Alkyl and Aryl Transferases
• geranylgeranyltransferase type-I
• p21(ras) farnesyl-protein transferase
• GTP Phosphohydrolases
• Rras protein, mouse
• rap1 GTP-Binding Proteins
• ras Proteins
• rhoA GTP-Binding Protein

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Animals
• Apoptosis (drug effects)
• Carrier Proteins (metabolism)
• Cell Differentiation (drug effects)
• Cell Transformation, Neoplastic (drug effects, metabolism)
• Enzyme Inhibitors (pharmacology)
• GTP Phosphohydrolases (metabolism)
• Genes, ras (genetics)
• HSP40 Heat-Shock Proteins
• Heat-Shock Proteins (metabolism)
• Imidazoles (pharmacology)
• Mammary Neoplasms, Experimental (drug therapy, enzymology, genetics, pathology)
• Mammary Tumor Virus, Mouse (genetics)
• Mice
• Mice, Transgenic
• Necrosis
• rap1 GTP-Binding Proteins (metabolism)
• ras Proteins (metabolism)
• rhoA GTP-Binding Protein (metabolism)