Heat Shock Protein 90 Inhibitor Induces Apoptosis and Attenuates Activation of Hepatic Stellate Cells

Myung, Sun Jung; Yoon, Jung Hwan; Kim, Bo Hyun; Lee, Jeong-Hoon; Jung, Eunjin; Lee, Hyo-Suk

doi:10.1124/jpet.109.151860

Cited by 44 publications

(23 citation statements)

References 41 publications

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“…17-AAG caused cell death via ceramide signaling in colorectal cancer HTC116 cells (Walker et al, 2010) and in human hepatic stellate cells (Myung et al, 2009). In contrast with ceramide, sphingosine-1-phosphate, a phosphorylated form of sphingosine, shows proliferative and anti-apoptotic effects (Posse de Chaves, 2006).…”

Section: Discussionmentioning

confidence: 99%

Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells

et al. 2012

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“…Targeting hsp90 to induce tumor cell apoptosis is currently in Phase I/II and III clinical trials for cancer therapy [9]. Hsp90 has also been reported as an attractive therapeutic target in hepatocellular carcinoma [10], is important in fibrosis [11] and facilitates hepatitis C virus replication during alcohol exposure [12, 13]. Similar to other stress signals, chronic alcohol induces hsp90 in the liver [14].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury

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Lim

et al. 2014

Journal of Hepatology

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Background & Aims Heat shock protein 90 (hsp90) is an emerging therapeutic target in chronic liver diseases. Hsp90 plays an important role in liver immune cell activation; however its role in alcoholic liver disease (ALD) remains elusive. Here we hypothesize that hsp90 is crucial in alcohol induced steatosis and pro-inflammatory cytokine production. To test this hypothesis, we employed a pharmacological inhibitor of hsp90, 17-DMAG [17-Dimethylamino-ethylamino-17-demethoxygeldanamycin] in an in vivo mouse model of acute and chronic alcoholic liver injury. Methods C57BL/6 mice were given either a single dose of ethanol via oral gavage (acute) or chronically fed alcohol for 2 weeks followed by oral gavage (chronic-binge). 17-DMAG was administered during or at the end of feeding. Liver injury parameters, inflammatory cytokines and lipid metabolism genes were analyzed. Results Our results reveal increased expression of hsp90 in human and mouse alcoholic livers. In vivo inhibition of hsp90, using 17-DMAG, not only prevents but also alleviates alcoholic liver injury, determined by lower serum ALT, AST and reduced hepatic triglycerides. Mechanistic analysis shows that 17-DMAG decreases alcohol mediated oxidative stress, reduces serum endotoxin, decreases inflammatory cells, and diminishes sensitization of liver macrophages to LPS, resulting in down-regulation of CD14, NFκB inhibition, and decreased pro-inflammatory cytokine production. Hsp90 inhibition decreases fatty acid synthesis genes via reduced nuclear SREBP-1 and favors fatty acid oxidation genes via PPARα. Conclusion Inhibition of hsp90 decreases alcohol induced steatosis and pro-inflammatory cytokines and inhibits alcoholic liver injury. Hsp90 is relevant in human alcoholic cirrhosis and promising therapeutic target in ALD.

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“…Ritonavir was also reported to deplete CDKs 2, 4, and 6 and cyclin D1 (14). Furthermore, both 17-AAG and ritonavir were shown to inhibit the transcription factor NF-κB (12,15) and cyclin D1 is a target gene of NF-κB (16). The combination of 17-AAG and ritonavir may thus act cooperatively to decrease the expression of cyclin D1 and CDK4 drastically, leading to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

17-allylamino-17-demethoxygeldanamycin and ritonavir inhibit renal cancer growth by inhibiting the expression of heat shock factor-1

2012

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Abstract. Our previous study showed that the combination of a histone deacetylase (HDAC) inhibitor and an HIV protease inhibitor is effective against renal cancer cells. Because HDAC inhibition disrupts the chaperon function of heat shock protein (HSP) 90, we hypothesized that the combination of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, and the HIV protease inhibitor ritonavir would also act against renal cancer. The combination of 17-AAG and ritonavir induced apoptosis and inhibited the proliferation of renal cancer cells effectively. It also suppressed the expression of cyclin-dependent kinase 4 and cyclin D1, leading to the accumulation of the cells in the sub-G1 fraction. The expression of HSPs 27, 70 and 90 was increased by 17-AAG alone but reduced by 17-AAG combined with ritonavir. The combination decreased the expression of heat shock factor-1 (HSF-1), an HSP transcription factor, and this might be one of the mechanisms of the effect of the combination. We have also found that silencing of HSF-1 by siRNA inhibited the proliferation of renal cancer cells and that in surgically resected specimens the levels of HSF-1 expression in renal cancer tissue are higher than those in normal parenchyma. This is the first study showing the beneficial effect of combining 17-AAG and ritonavir and our data suggest that HSF-1 may be a novel therapeutic target in the treatment of renal cancer. IntroductionAlthough recently introduced novel anticancer agents such as inhibitors of tyrosine kinase (1,2) and the mammalian target of rapamycin (3) are promising against advanced renal cancer, new treatment approaches are needed because curative agents are not yet available.Inhibition of heat shock protein 90 (HSP90) destabilizes the cancer cell's aberrant protein subset, leading to protein degradation by proteasomes (4). The geldanamycin derivative 17-allylamino-17-demethoxy-geldanamycin (17-AAG) is the first HSP90 inhibitor to be used clinically (5). It seems to be a promising anticancer agent with a novel mechanism of action, but a phase II clinical trial investigating the efficacy of 17-AAG found it not to be effective against renal cancer (6).We have previously shown that the combination of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and the HIV protease inhibitor ritonavir is effective against renal cancer by inhibiting the HDAC function and expression, leading to extensive histone acetylation (7). SAHA inhibits HDAC6, and ablation of HDAC6 has been shown to induce hyperacetylation of HSP 90, disrupting its chaperone function (8,9). We therefore thought that combining ritonavir with 17-AAG would be more effective against renal cancer because 17-AAG could inhibit HSP90 function more directly than SAHA does.In the present study, we investigated the combined effect of 17-AAG and ritonavir against renal cancer by using renal cancer cell lines and found that the combination inhibited the renal cancer growth by inhibiting the expression of heat shock factor-1 (HSF-1), an HS...

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Heat Shock Protein 90 Inhibitor Induces Apoptosis and Attenuates Activation of Hepatic Stellate Cells

Cited by 44 publications

References 41 publications

Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells

Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells

Inhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury

17-allylamino-17-demethoxygeldanamycin and ritonavir inhibit renal cancer growth by inhibiting the expression of heat shock factor-1

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