Does endoplasmic reticulum stress participate in APD-induced hepatic metabolic dysregulation?

Lauressergues, Emilie; Bert, Elodie; Duriez, Patrick; Hum, Dean W.; Majd, Zouher; Staels, Bart; Cussac, Didier

doi:10.1016/j.neuropharm.2011.08.048

Cited by 64 publications

(45 citation statements)

References 71 publications

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“…Our results strongly indicate that TM induced a significant increase in the relative mRNA expression of genes involved in the ER stress in goose primary hepatocytes. This result is consistent with the findings in mouse (Wang et al, 2015) and immortalized human hepatocyte cell model (IHH; Lauressergues et al, 2012). PI3K/Akt signaling has been reported to be involved in the ER stress (Liu et al, 2013).…”

Section: Discussionsupporting

confidence: 92%

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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Section: Discussionsupporting

confidence: 92%

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

et al. 2016

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“…20 Interestingly, antipsychotic drugs such as clozapine, haloperidol, olanzapine, and risperidone are known to induce ER stress. 8,21 ER stress has been linked to induce autophagy-mediated cell death in cancer. Several antipsychotic drugs such as fluspirilene, trifluoperazine, and pimozide are known to induce autophagy.…”

Section: Discussionmentioning

confidence: 99%

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

et al. 2017

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Pancreatic cancer is one of the most aggressive and difficult to treat cancers. Experimental and clinical evidence suggests that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapy. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis both in vitro and in vivo; however, the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum stress could lead to autophagy and inhibit tumor progression. In this study, we demonstrated that penfluridol induced endoplasmic reticulum stress in BxPC-3, AsPC-1, and Panc-1 pancreatic cancer cell lines as indicated by upregulation of endoplasmic reticulum stress markers such as binding protein (BIP), C/EBP homologous protein (CHOP) and inositol requiring 1α (IRE1α) after treatment with penfluridol in a concentration-dependent manner. Inhibiting endoplasmic reticulum stress by pretreatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOP small interfering RNA, blocked penfluridol-induced autophagy. These results clearly indicate that penfluridol-induced endoplasmic reticulum stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP, and IRE1α expression in the tumor lysates from penfluridol-treated mice as compared to tumors from control mice. Altogether, our study establishes that penfluridol-induced endoplasmic reticulum stress leads to autophagy resulting in reduced pancreatic tumor growth. Our study opens a new therapeutic target for advanced chemotherapies against pancreatic cancer.

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“…It was found that certain atypical antipsychotic drugs induce endoplasmic reticulum stress via changes in Ca++ homeostasis in hepatocytes. This effect was considered as a part of their undesirable hepatic metabolic side effects [35] .…”

Section: Discussionmentioning

confidence: 99%

Histological Study of the Effects of Olanzapine on the Liver of Adult Male Albino Rat with and without Vitamin C

Elbakary

2017

Egyptian Journal of Histology

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Introduction: Olanzapine is an atypical antipsychotic drug widely used in treatment of schizophrenia for prolonged time. Aim of the work: The present study was carried out to evaluate the effect of olanzapine on the liver and the possible protective effect of vitamin C. Material and Methods: Forty adult male albino rats were used in this work. They were divided into: Group I as a control, group II was given Olanzapine (2mg/kg B. wt. orally once daily) for one month, group III was given Olanzapine (at the same previous dose) plus vitamin C (15 mg /Kg. B. wt of orally once daily) for one month and group IV was given only vitamin C (for the same dose and period of the previous group). At the end of the experiment, liver specimens were processed for histological study by light and electron microscopes. Also blood samples were collected for estimation of liver enzymes. Result: Significant increase in the level of liver enzymes was observed in Olanzapine treated group. While the microscopic examination of the liver sections of this group revealed several histological changes including, dilatation and congestion of central veins and blood sinusoids, inflammatory cellular infiltration in the portal areas and cytoplasmic vacuolation of hepatocytes that present mainly around the central veins. Mitochondrial degeneration, bile ducts dilatation and excessive deposition of lipid droplets were also observed. These changes were ameliorated by vitamin C administration. Conclusion: Results of this experimental work revealed that administration of vitamin C greatly reduced the histological alterations induced by Olanzapine, suggesting that vitamin C has a protective effect on the liver.

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Does endoplasmic reticulum stress participate in APD-induced hepatic metabolic dysregulation?

Cited by 64 publications

References 71 publications

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

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

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

Histological Study of the Effects of Olanzapine on the Liver of Adult Male Albino Rat with and without Vitamin C

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