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K-Ras-independent effects of the farnesyl transferase inhibitor L-744,832 on cyclin B1/Cdc2 kinase activity, G2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cells

 Si-Young Song  ;  Ingrid M. Meszoely  ;  Robert J. Coffey  ;  Jennifer A. Pietenpol  ;  Steven D. Leach 
 Neoplasia, Vol.2(3) : 261-272, 2000 
Journal Title
Issue Date
Antineoplastic Agents/pharmacology* ; Apoptosis/drug effects* ; Carcinoma, Ductal, Breast/pathology* ; Cyclin B/metabolism* ; Cyclin B1 ; Enzyme Inhibitors/pharmacology* ; G2 Phase/drug effects ; Genes, ras/physiology* ; Humans ; Methionine/analogs & derivatives* ; Methionine/pharmacology ; Mitosis/drug effects ; Pancreatic Neoplasms/pathology*
farnesylation ; cyclin B/cdc2 ; mitosis ; pancreas ; cancer
Pancreatic ductal adenocarcinoma is a highly lethal malignancy that is resistant to traditional cytotoxic therapy. High rates of activating codon 12 K-Ras mutations in this disease have generated considerable interest in the therapeutic application of novel farnesyl transferase inhibitors (FTIs). However, a comprehensive analysis of the effects of FTI treatment on pancreatic cancer cells has not been performed. Treatment of five different human pancreatic cancer cell lines with FTI L-744,832 resulted in inhibition of anchorage-dependent growth, with wide variation in sensitivity among different lines. Effective growth inhibition by L-744,832 correlated with accumulation of cells with a tetraploid (4N) DNA content and high levels of cyclin B1/cdc2 kinase activity, implying cell cycle arrest downstream from the DNA damage-inducible G2/M cell cycle checkpoint. In addition, sensitive cell lines underwent apoptosis as evidenced by changes in nuclear morphology and internucleosomal DNA fragmentation. L-744,832 at a concentration of 1 microM additively enhanced the cytotoxic effect of ionizing radiation, apparently by overriding G2/M checkpoint activation. The effects of FTI treatment on cell growth and cell cycle regulation were associated with changes in posttranslational processing of H-Ras and N-Ras, but not K-Ras. The results confirm the potential therapeutic efficacy of FTI treatment in pancreatic cancer, and suggest that farnesylated proteins other than K-Ras may act as important regulators of G2/M cell cycle kinetics.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Song, Si Young(송시영) ORCID logo https://orcid.org/0000-0002-1417-4314
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