The mechanism of geranylgeraniol-induced apoptosis involves activation, by a caspase-3-like protease, of a c-jun N-terminal kinase signaling cascade and differs from mechanisms of apoptosis induced by conventional chemotherapeutic drugs.

Abstract

In the present study, we investigated the effects of geranylgeraniol (GGO), a potent inducer of apoptosis in various lines of human tumor cells, on signal transduction cascades involved in apoptosis in human leukemia cells. GGO strongly induced the activation of c-Jun N-terminal kinase (JNK/SAPK) within 2 h in U937 and K562 cells, while neither ERK nor p38 was activated to any considerable extent during GGO-induced apoptosis. Transient expression of a constitutively active mutant form of mitogen-activated protein kinase kinase 1 (MEKK1), deltaMEKK1, or of deltaMEKK1-green fluorescent protein (GFP) in K562 cells activated JNK, but not a caspase-3-like protease, and was insufficient to induce cell death but rendered cells susceptible to GGO-induced cell death. Stable expressions of deltaMEKK1-GFP in U937 cells gave similar results. In contrast to VP-16-induced apoptosis, GGO-induced activation of JNK was almost completely inhibited by benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD) and by benzyloxycarbonyl-Asp-CH2OC[O]-2,6,-dichlorobenzene (Z-Asp), indicating that the JNK-activation step is located downstream of the caspase signaling pathway in GGO-induced apoptosis. Moreover, apoptosis induced by GGO was significantly inhibited in two lines of cells with a dominant-negative deletion mutation in c-Jun, indicating a requirement for JNK signaling. In addition, unlike the effects on other inducers of apoptosis, the activation of JNK and of the caspase-3-like protease by GGO was significantly delayed by 12-O-tetradecanoylphorbol-13-acetate (TPA), suggesting that the site of inhibition by TPA might be located upstream of the protease and JNK in the GGO-induced apoptotic signaling pathway.

• Authors: Y Masuda, M Nakaya, T Aiuchi, S Hashimoto, S Nakajo, K Nakaya
• Journal: Leukemia research (Leuk Res) Vol. 24 Issue 11 Pg. 937-50 (Nov 2000) ISSN: 0145-2126 [Print] England
• PMID: 11086177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cysteine Proteinase Inhibitors
• Diterpenes
• Luminescent Proteins
• Recombinant Fusion Proteins
• Green Fluorescent Proteins
• geranylgeraniol
• Protein Serine-Threonine Kinases
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 1
• MAP3K1 protein, human
• CASP3 protein, human
• Caspase 3
• Caspases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Caspase 3
• Caspases (metabolism)
• Cysteine Proteinase Inhibitors (pharmacology)
• Diterpenes (pharmacology)
• Green Fluorescent Proteins
• Humans
• JNK Mitogen-Activated Protein Kinases
• K562 Cells
• Luminescent Proteins (genetics)
• MAP Kinase Kinase Kinase 1
• MAP Kinase Signaling System (drug effects, physiology)
• Mitogen-Activated Protein Kinases (metabolism)
• Mutagenesis
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Recombinant Fusion Proteins (biosynthesis)
• Sequence Deletion
• Transfection
• U937 Cells