Geldanamycin induction of grp78 requires activation of reactive oxygen species via ER stress responsive elements in 9L rat brain tumour cells

Lai, Ming-Tsong; Huang, Kai‐Lin; Chang, Whei-meih; Lai, Yiu‐Kay

doi:10.1016/s0898-6568(03)00004-4

Cited by 32 publications

(26 citation statements)

References 47 publications

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“…Initially, from the minor ROS induction that arose from the internal GA control (Fig. 4), we ruled out the possibility of GA generating ROS via an Hsp90-independent mechanism, although GA did increase the level of ROS from macrophages compared with the control as at ASPET Journals on May 11, 2018 molpharm.aspetjournals.org reported previously (Dikalov et al, 2002;Lai et al, 2003). Our previous studies indicated that membrane-bound NADPH oxidase is one of the main sources of LPS-induced ROS (Hsu and Wen, 2002) and that pretreatment of macrophages with GA-enhancing LPS-induced ROS release is probably relevant to the activation of NADPH oxidase.…”

Section: Geldanamycin Inhibition Of Macrophage Hsp90 In Apoptosis 353mentioning

confidence: 78%

Geldanamycin Interferes with the 90-kDa Heat Shock Protein, Affecting Lipopolysaccharide-Mediated Interleukin-1 Expression and Apoptosis within Macrophages

Hsu¹,

Wu²,

Tan³

et al. 2006

Mol Pharmacol

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We have demonstrated that lipopolysaccharide (LPS)-mediated reactive oxygen species (ROS) and signal transduction are involved in the regulation of interleukin-1 (IL-1) ␤ gene expression within macrophages. Because the 90-kDa heat shock protein (Hsp90) plays an important role in the LPS mediation of macrophage activation, using Hsp90 inhibitor geldanamycin A (GA), we analyzed the mechanism of Hsp90 upon LPS-transduced signaling in the regulation of IL-1 expression and determined the function of Hsp90 regarding the viability of human primary macrophages and murine macrophages cell line. In essence, GA decreased LPS-induced Hsp90/pp60Src heterocomplex formation. In addition, Hsp90 is important for IL-1 protein translation, plays a minor role in IL-1 mRNA transcription, and is involved in nuclear factor-B activation and the phosphorylation and activation of p38, c-Jun NH 2 -terminal kinase, and extracellular signalregulated kinase; however, Hsp90 plays a more important role in LPS-stimulated p38 activation. In analyzing the function of Hsp90 regarding the cytotoxicity/viability of macrophages, we found that the combination of LPS and GA increases apoptosis, as evidenced by the increased caspase-3 activity and the proportion of nuclear/chromatin condensation. In contrast, N-acetyl-cysteine dramatically blocked GA/LPS-induced ROS production, simultaneously decreasing caspase-3 activity and the presence of apoptotic nuclei. We concluded that Hsp90 plays an indispensable role in the process of LPS-induced IL-1 secretion. Furthermore, we established the mechanism of GA interference with Hsp90 function for LPS-stimulated macrophages, resulting in increased ROS production and caspase-3 activation, and consequently leading to synergistic enhancement of macrophage apoptosis.

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Section: Geldanamycin Inhibition Of Macrophage Hsp90 In Apoptosis 353mentioning

confidence: 78%

Geldanamycin Interferes with the 90-kDa Heat Shock Protein, Affecting Lipopolysaccharide-Mediated Interleukin-1 Expression and Apoptosis within Macrophages

Hsu¹,

Wu²,

Tan³

et al. 2006

Mol Pharmacol

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“…It provides a site for protein modification and folding as well as functions as an intracellular Ca 2+ store that plays a central role in signal transduction (Galligan et al, 2012;Pagliassotti, 2012). However, when oxidative stress, chemical toxicity, hepatic viral infections, metabolic disorders, and abuse of alcohol or drugs cause accumulation of unfolded proteins in the ER lumen and disrupt the intracellular Ca 2+ homeostasis (Lai et al, 2003;Rao et al, 2004;Schröder and Kaufman, 2005b), ER stress occurs. In order to restore ER homeostasis, liver cells down-regulate the overall protein synthesis through an adaptive protective response termed the unfolded protein response (UPR) signaling system, which involves enhancement of protein folding and degradation in the ER (Shen et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

PI3K-Akt-mTOR signal inhibition affects expression of genes related to endoplasmic reticulum stress

et al. 2016

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ABSTRACT. PI3K-Akt-mTOR signaling pathway is associated with endoplasmic reticulum (ER) stress. However, it is not clear how this signaling pathway affects the ER stress. The present study aimed to determine whether the PI3K-Akt-mTOR signaling pathway regulates tunicamycin (TM)-induced increases in mRNA levels of genes involved in the ER stress, to help elucidate the mechanism by which this pathway affects the ER stress in primary goose hepatocytes. Primary hepatocytes were isolated from geese and cultured in vitro. After 12 h in a serumfree medium, the hepatocytes were incubated for 24 h in a medium with either no addition (control) or with supplementation of TM or TM together with PI3K-Akt-mTOR signaling pathway inhibitors (LY294002, rapamycin, NVP-BEZ235). Thereafter, the expression levels of genes involved in the ER stress (BIP, EIF2a, ATF6, and XBP1) were assessed. The results indicated that the mRNA level of BIP 2 Q. Song et al. Genetics and Molecular Research 15 (3): gmr.15037868 was up-regulated in 0.2, 2, and 20 µM TM treatment group (P < 0.05), whereas the mRNA levels of EIF2a, ATF6, and XBP1 were up-regulated in the 2 µM TM treatment group (P < 0.05). However, the TM mediated induction of mRNA levels of genes involved in the ER stress (BIP, EIF2a, ATF6, and XBP1) was down-regulated after the treatment with PI3K-Akt-mTOR pathway inhibitors (LY294002, NVP-BEZ235, and rapamycin). Therefore, our results strongly suggest that the PI3K-AktmTOR signaling pathway might be involved in the down-regulation of the TM-induced ER stress in primary goose hepatocytes.

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“…Treatment of tumor cells with GA results in proteasome-mediated degradation of Hsp90 client proteins. In addition, cytotoxicity of GA on tumors has also been attributed to ROS generation (Dikalov et al, 2002;Lai et al, 2003). Despite potent cytotoxicity on tumors, lethal hepatotoxicity in animals limits the promise of GA as a drug candidate.…”

mentioning

confidence: 99%

Cystine-Glutamate Transporter SLC7A11 Mediates Resistance to Geldanamycin but Not to 17-(Allylamino)-17-demethoxygeldanamycin

Liu

Blower²,

Pham³

et al. 2007

Mol Pharmacol

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Geldanamycin induction of grp78 requires activation of reactive oxygen species via ER stress responsive elements in 9L rat brain tumour cells

Cited by 32 publications

References 47 publications

Geldanamycin Interferes with the 90-kDa Heat Shock Protein, Affecting Lipopolysaccharide-Mediated Interleukin-1 Expression and Apoptosis within Macrophages

Geldanamycin Interferes with the 90-kDa Heat Shock Protein, Affecting Lipopolysaccharide-Mediated Interleukin-1 Expression and Apoptosis within Macrophages

PI3K-Akt-mTOR signal inhibition affects expression of genes related to endoplasmic reticulum stress

Cystine-Glutamate Transporter SLC7A11 Mediates Resistance to Geldanamycin but Not to 17-(Allylamino)-17-demethoxygeldanamycin

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