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 Hamilton, Saïd M. Sebti

Research output: Contribution to journalArticle

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

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Farnesyltranstransferase
Transgenic Mice
Apoptosis
Breast Neoplasms
Neoplasms
rhoA GTP-Binding Protein
ras Proteins
Drug Discovery
Carcinogenesis
Breast
Epithelium
geranylgeranyltransferase type-I
GGTI-2154
Growth
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sun, J., Ohkanda, J., Coppola, D., Yin, H., Kothare, M., Busciglio, B., ... Sebti, S. M. (2003). Geranylgeranyltransferase I Inhibitor GGTI-2154 Induces Breast Carcinoma Apoptosis and Tumor Regression in H-Ras Transgenic Mice. Cancer Research, 63(24), 8922-8929.

Geranylgeranyltransferase I Inhibitor GGTI-2154 Induces Breast Carcinoma Apoptosis and Tumor Regression in H-Ras Transgenic Mice. / Sun, Jiazhi; Ohkanda, Junko; Coppola, Domenico; Yin, Hang; Kothare, Mohit; Busciglio, Brian; Hamilton, Andrew; Sebti, Saïd M.

In: Cancer Research, Vol. 63, No. 24, 15.12.2003, p. 8922-8929.

Research output: Contribution to journalArticle

Sun, J, Ohkanda, J, Coppola, D, Yin, H, Kothare, M, Busciglio, B, Hamilton, A & Sebti, SM 2003, 'Geranylgeranyltransferase I Inhibitor GGTI-2154 Induces Breast Carcinoma Apoptosis and Tumor Regression in H-Ras Transgenic Mice', Cancer Research, vol. 63, no. 24, pp. 8922-8929.
Sun J, Ohkanda J, Coppola D, Yin H, Kothare M, Busciglio B et al. Geranylgeranyltransferase I Inhibitor GGTI-2154 Induces Breast Carcinoma Apoptosis and Tumor Regression in H-Ras Transgenic Mice. Cancer Research. 2003 Dec 15;63(24):8922-8929.
Sun, Jiazhi ; Ohkanda, Junko ; Coppola, Domenico ; Yin, Hang ; Kothare, Mohit ; Busciglio, Brian ; Hamilton, Andrew ; Sebti, Saïd M. / Geranylgeranyltransferase I Inhibitor GGTI-2154 Induces Breast Carcinoma Apoptosis and Tumor Regression in H-Ras Transgenic Mice. In: Cancer Research. 2003 ; Vol. 63, No. 24. pp. 8922-8929.
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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.",
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