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Phenethyl isothiocyanate, a natural chemopreventive agent, activates c-Jun N-terminal kinase 1
1Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois, Chicago 60612, USA.
Abstract:
Phenethyl isothiocyanate (PEITC) and other structurally related compounds are potent chemopreventive agents in a number of experimental models of cancer in animals. The mechanisms of cancer protection by these agents are not clear but may involve the regulation of gene expression, such as that by Phase II detoxifying enzymes. To unveil the upstream signaling events that lead to the potential transcriptional activation of genes, we studied the involvement of mitogen-activated protein kinase, c-Jun N-terminal kinase 1 (JNK1), and extracellular signal-regulated kinase 1 and 2 cascades, which have been shown to mediate numerous types of extracellular signals. On treatment of human ovarian HeLa cells with PEITC, JNK1 activity was strongly induced in a dose- and time-dependent manner, whereas the activation of extracellular signal-regulated kinase 1 and 2 was not substantial. Furthermore, activation of JNK1 by PEITC was inhibited by pro-oxidants hydrogen peroxide and diamide, although these two pro-oxidants by themselves had opposing effects on JNK1 activity. Pretreatment with an antioxidant, N-acetyl-L-cysteine, had no effects on PEITC activation of JNK1. When comparing the kinetics of JNK1 activation by different isothiocyanates, PEITC elicited a sustained activation, whereas 3-phenylpropyl isothiocyanate and 4-phenylbutyl isothiocyanate stimulated transient activations. The responsiveness of JNK1 to PEITC, 3-phenylpropyl isothiocyanate, and 4-phenylbutyl isothiocyanate suggests the involvement of JNK1 in the regulation of Phase II detoxifying enzyme gene expression. Furthermore, different patterns of JNK1 induction by these isothiocyanates may contribute to their distinct chemopreventive efficacies in some animal tumor model studies.
Insights
Phenethyl isothiocyanate (PEITC) activates c-Jun N-terminal kinase 1 (JNK1) signaling, suggesting a role in cancer chemoprevention through gene expression regulation. Different isothiocyanates show varied JNK1 activation patterns, potentially explaining distinct efficacies.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- Phenethyl isothiocyanate (PEITC) and related compounds show chemopreventive effects in animal cancer models.
- Mechanisms of PEITC's cancer protection are unclear but may involve gene expression regulation, including Phase II detoxifying enzymes.
Purpose of the Study:
- To investigate upstream signaling events, specifically mitogen-activated protein kinase (MAPK) pathways like c-Jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated kinase 1 and 2 (ERK1/2), involved in PEITC-induced gene expression.
- To elucidate the role of JNK1 and ERK1/2 cascades in mediating PEITC's cellular effects.
Main Methods:
- Human ovarian HeLa cells were treated with PEITC.
- JNK1 and ERK1/2 activities were measured.
- Effects of pro-oxidants (hydrogen peroxide, diamide) and an antioxidant (N-acetyl-L-cysteine) on JNK1 activation were assessed.
- Kinetics of JNK1 activation by PEITC and related isothiocyanates were compared.
Main Results:
- PEITC strongly induced JNK1 activity in a dose- and time-dependent manner in HeLa cells.
- ERK1/2 activation by PEITC was not substantial.
- Pro-oxidants inhibited PEITC-induced JNK1 activation, while antioxidants had no effect.
- PEITC induced sustained JNK1 activation, contrasting with transient activation by 3-phenylpropyl isothiocyanate and 4-phenylbutyl isothiocyanate.
Conclusions:
- JNK1 activation by PEITC and related isothiocyanates suggests JNK1's involvement in regulating Phase II detoxifying enzyme gene expression.
- Distinct JNK1 activation patterns by different isothiocyanates may correlate with their varying chemopreventive efficacies in animal tumor models.