Proteasome inhibition induces hepatic stellate cell apoptosis

Akira Anan, Edwina S. Baskin-Bey, Steven F. Bronk, Nathan W. Werneburg, Vijay Shah, Gregory James Gores

Research output: Contribution to journalArticle

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Abstract

Induction of hepatic stellate cell (HSC) apoptosis attenuates hepatic fibrosis, and, therefore, mechanisms to induce HSC cell death are of therapeutic interest. Proteasome inhibitors induce apoptosis in transformed cells, especially those cells dependent upon nuclear factor kappa B (NF-κB) activation. Because stimulated HSCs also trigger NF-κB activation, the aim of this study was to determine if proteasome inhibitors induce HSC apoptosis. The immortalized human HSC line, LX-2, and primary rat HSCs were treated with the proteasome inhibitors bortezomib and MG132. Both proteasome inhibitors induced HSC apoptosis. Proteasome inhibition blocked NF-κB activation and, more importantly, NF-κB inhibition by Bay11-7082-triggered HSC apoptosis. Activated HSC survival is dependent upon the NF-κB target gene A1, an anti-apoptotic Bcl-2 family member, as siRNA targeted knockdown of A1-induced HSC apoptosis. In contrast, proteasome inhibition-induced alterations in TRAIL, death receptor 5, and Bim could not be implicated in the apoptotic response. The relevance of these findings was confirmed in the bile-duct-ligated mouse where bortezomib reduced hepatic markers of stellate cell activation and fibrosis. In conclusion, proteasome inhibition is a potential therapeutic strategy for inducing HSC apoptosis and inhibiting liver fibrogenesis.

Original languageEnglish (US)
Pages (from-to)335-344
Number of pages10
JournalHepatology
Volume43
Issue number2
DOIs
StatePublished - Feb 2006

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Hepatic Stellate Cells
Proteasome Endopeptidase Complex
Apoptosis
NF-kappa B
Proteasome Inhibitors
TNF-Related Apoptosis-Inducing Ligand Receptors
Fibrosis
Inhibition (Psychology)
Liver
Bile Ducts
Small Interfering RNA
Cell Survival
Cell Death
Cell Line

ASJC Scopus subject areas

  • Hepatology

Cite this

Anan, A., Baskin-Bey, E. S., Bronk, S. F., Werneburg, N. W., Shah, V., & Gores, G. J. (2006). Proteasome inhibition induces hepatic stellate cell apoptosis. Hepatology, 43(2), 335-344. https://doi.org/10.1002/hep.21036

Proteasome inhibition induces hepatic stellate cell apoptosis. / Anan, Akira; Baskin-Bey, Edwina S.; Bronk, Steven F.; Werneburg, Nathan W.; Shah, Vijay; Gores, Gregory James.

In: Hepatology, Vol. 43, No. 2, 02.2006, p. 335-344.

Research output: Contribution to journalArticle

Anan, A, Baskin-Bey, ES, Bronk, SF, Werneburg, NW, Shah, V & Gores, GJ 2006, 'Proteasome inhibition induces hepatic stellate cell apoptosis', Hepatology, vol. 43, no. 2, pp. 335-344. https://doi.org/10.1002/hep.21036
Anan, Akira ; Baskin-Bey, Edwina S. ; Bronk, Steven F. ; Werneburg, Nathan W. ; Shah, Vijay ; Gores, Gregory James. / Proteasome inhibition induces hepatic stellate cell apoptosis. In: Hepatology. 2006 ; Vol. 43, No. 2. pp. 335-344.
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