The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis

Kun Jiang, Domenico Coppola, Nichole C. Crespo, Santo V. Nicosia, Andrew Hamilton, Said M. Sebti, Jin Q. Cheng

Research output: Contribution to journalArticle

Abstract

Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs that exhibit a remarkable ability to inhibit malignant transformation without toxicity to normal cells. However, the mechanism by which FTIs inhibit tumor growth is not well understood. Here, we demonstrate that FTI-277 inhibits phosphatidylinositol 3-OH kinase (PI 3-kinase)/AKT2- mediated growth factor- and adhesion-dependent survival pathways and induces apoptosis in human cancer cells that overexpress AKT2. Furthermore, overexpression of AKT2, but not oncogenic H-Ras, sensitizes NIH 3T3 cells to FTI-277, and a high serum level prevents FTI-277-induced apoptosis in H-Ras- but not AKT2-transformed NIH 3T3 cells. A constitutively active form of AKT2 rescues human cancer cells from FTI-277-induced apoptosis. FTI-277 inhibits insulin-like growth factor 1-induced PI 3-kinase and AKT2 activation and subsequent phosphorylation of the proapoptotic protein BAD. Integrin- dependent activation of AKT2 is also blocked by FTI-277. Thus, a mechanism for FTI inhibition of human tumor growth is by inducing apoptosis through inhibition of PI 3-kinase/AKT2-mediated cell survival and adhesion pathway.

Original languageEnglish (US)
Pages (from-to)139-148
Number of pages10
JournalMolecular and Cellular Biology
Volume20
Issue number1
StatePublished - Jan 2000

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Farnesyltranstransferase
Phosphatidylinositols
Phosphotransferases
Apoptosis
Phosphatidylinositol 3-Kinases
NIH 3T3 Cells
Neoplasms
Somatomedins
Growth
Cell Adhesion
Integrins
Cell Survival
Intercellular Signaling Peptides and Proteins
Phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Jiang, K., Coppola, D., Crespo, N. C., Nicosia, S. V., Hamilton, A., Sebti, S. M., & Cheng, J. Q. (2000). The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Molecular and Cellular Biology, 20(1), 139-148.

The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. / Jiang, Kun; Coppola, Domenico; Crespo, Nichole C.; Nicosia, Santo V.; Hamilton, Andrew; Sebti, Said M.; Cheng, Jin Q.

In: Molecular and Cellular Biology, Vol. 20, No. 1, 01.2000, p. 139-148.

Research output: Contribution to journalArticle

Jiang, K, Coppola, D, Crespo, NC, Nicosia, SV, Hamilton, A, Sebti, SM & Cheng, JQ 2000, 'The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis', Molecular and Cellular Biology, vol. 20, no. 1, pp. 139-148.
Jiang, Kun ; Coppola, Domenico ; Crespo, Nichole C. ; Nicosia, Santo V. ; Hamilton, Andrew ; Sebti, Said M. ; Cheng, Jin Q. / The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. In: Molecular and Cellular Biology. 2000 ; Vol. 20, No. 1. pp. 139-148.
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