Geranylgeranyltransferase I Inhibitor GGTI-2154 Induces Breast Carcinoma Apoptosis and Tumor Regression in H-Ras Transgenic Mice

Jiazhi Sun, Junko Ohkanda, Domenico Coppola, Hang Yin, Mohit Kothare, Brian Busciglio, Andrew D. Hamilton, Saïd M. Sebti

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)8922-8929
Number of pages8
JournalCancer Research
Volume63
Issue number24
StatePublished - Dec 15 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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