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PMID: 10594016 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Molecular and cellular biology ·Vol. 20 ·No. 1 ·2000-01-00 ·Pages 139-48

Jiang K, Coppola D, Crespo NC, Nicosia SV, Hamilton AD, Sebti SM, Cheng JQ

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.

MeSH Terms
Alkyl and Aryl Transferases/antagonists & inhibitors,metabolism Apoptosis/drug effects Cell Line Enzyme Inhibitors/pharmacology Farnesyltranstransferase Female Humans Methionine/analogs & derivatives,pharmacology Phosphatidylinositol 3-Kinases/metabolism Protein Serine-Threonine Kinases Protein-Tyrosine Kinases/metabolism Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-akt Signal Transduction/drug effects
Chemicals
Enzyme Inhibitors FTI 277 Proto-Oncogene Proteins Methionine Alkyl and Aryl Transferases Farnesyltranstransferase Protein-Tyrosine Kinases AKT2 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Jiang K
Department of Pathology, College of Medicine, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida 33612, USA.
Coppola D
Crespo N C
Nicosia S V
Hamilton A D
Sebti S M
Cheng J Q
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.20.1.139-148.2000
Published
2000-01-00
Pages
139-48
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC85069
Subset
IM
Grants
NCI NIH HHS · CA-67771 · United States
NCI NIH HHS · R29 CA077935 · United States
NCI NIH HHS · R01 CA077935 · United States
NCI NIH HHS · CA-77935 · United States
NCI NIH HHS · U19 CA067771 · United States
External Links
PubMed source DOI: 10.1128/MCB.20.1.139-148.2000 PMC Full Text View journal details
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