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Two naturally occurring terpenes, dehydrocostuslactone and costunolide, decrease intracellular GSH content and

Elena Butturini¹, Elisabetta Cavalieri, Alessandra Carcereri de Prati

¹Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.

|June 1, 2011

Summary

Dehydrocostuslactone (DCE) and costunolide (CS) inhibit signal transducer and activator of transcription 3 (STAT3) activation by depleting glutathione and causing S-glutathionylation. This redox-dependent modification regulates STAT3 function.

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Area of Science:

Biochemistry
Molecular Biology
Pharmacology

Background:

Signal transducer and activator of transcription 3 (STAT3) is a key regulator of cellular processes.
Dysregulated STAT3 activation is implicated in various diseases, making it a therapeutic target.
Sesquiterpene lactones are natural compounds with diverse biological activities.

Purpose of the Study:

To elucidate the molecular mechanism by which dehydrocostuslactone (DCE) and costunolide (CS) inhibit STAT3 activation.
To investigate the role of the α-β-unsaturated carbonyl moiety in the inhibitory action of these compounds.
To explore the redox-dependent regulation of STAT3 by DCE and CS.

Main Methods:

Inhibition assays using human THP-1 cell line.
Measurement of STAT3 tyrosine phosphorylation and DNA binding activity.
Assessment of Janus kinase (JAK) phosphorylation (JAK1, JAK2, Tyk2).
Quantification of intracellular glutathione (GSH) levels.
Analysis of S-glutathionylation of STAT3.
Evaluation of the effect of dehydrocostunolide (HCS) and glutathione ethylene ester (GEE).

Main Results:

DCE and CS inhibited IL-6-elicited STAT3 tyrosine phosphorylation and DNA binding activity (EC50 = 10 µM).
These compounds down-regulated the phosphorylation of JAK1, JAK2, and Tyk2.
DCE and CS induced a rapid decrease in intracellular GSH by direct interaction, leading to STAT3 S-glutathionylation.
HCS, lacking the α-β-unsaturated carbonyl group, did not inhibit STAT3.
GEE reversed the inhibitory effects of DCE and CS on STAT3 phosphorylation.

Conclusions:

DCE and CS inhibit STAT3 activation through a redox-dependent mechanism.
The α-β-unsaturated carbonyl moiety is crucial for the activity of these sesquiterpene lactones.
STAT3 function is regulated by redox-dependent post-translational modification of its cysteine residues.