Phosphorylation of eIF2α mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury

Tian, Ren-Dong; Chen, Yiqun; He, Yi-Huai; Tang, Yong-Jing; Chen, Gui-Mei; Yang, Feifei; Liu, Ying; Huang, Weicai; Chen, Huan; Liu, Xia; Lin, Shide

doi:10.1016/j.aohep.2019.05.008

Cited by 26 publications

(22 citation statements)

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“…ER stress is closely related to cell apoptosis, necroptosis and cell proliferation [26][27][28]. Earlier, we reported that ER stress affects hepatocyte apoptosis [24], necroptosis [22] and cell proliferation [23,29]. In this study, TG induced ER stress, triggered apoptosis and necroptosis, and inhibited cell proliferation in hepatocellular carcinoma cells.…”

Section: Discussionsupporting

confidence: 51%

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Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells

Chen

Liu

et al. 2021

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Alpha-fetoprotein (AFP) and endoplasmic reticulum (ER) stress play multiple roles in hepatocellular carcinoma. Here, we analyzed the crosstalk between AFP and ER stress in human hepatoma cells. We induced ER stress in human hepatoma cell lines (HepG2 and SK-Hep1 cells) with thapsigargin (TG, an ER stress inducer), and mitigated ER stress with 4-phenylbutyrate acid (4-PBA, an ER stress inhibitor). AFP expression was knocked down by AFP short hairpin RNA and rescued by the pCI-AFP vector. AFP expression and ER stress were examined, and their roles in apoptosis, necroptosis, and proliferation were analyzed. TG significantly induced ER stress, apoptosis, necroptosis, and intracellular AFP protein levels, and reduced proliferation and AFP mRNA expression as well as supernatant AFP protein levels in HepG2 and SK -Hep1 cells. 4-PBA pretreatment partially reversed those changes in HepG2 cells. By contrast to AFP overexpression, knockdown of AFP significantly exacerbated TG-induced ER stress, apoptosis, and necroptosis, and decreased proliferation and the expression of activating transcription factor 6 alpha. In conclusion, ER stress causes the accumulation of AFP protein, which may be related to the reduction of AFP secretion. Accumulated AFP mitigates apoptosis and necroptosis and restores the proliferation of hepatoma cells by reducing ER stress.

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Section: Discussionsupporting

confidence: 51%

“…Subsequently, the isolated RNA (500 ng (TaKaRa), and qPCR was completed on the CFX96 PCR system (Bio-Rad). Relative AFP expression was estimated with the delta-delta-GAPDH as the reference control [22].…”

Section: Methodsmentioning

confidence: 99%

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells

Chen

Liu

et al. 2021

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“…Various methods, including pharmacological inhibition and gene knockout and knockdown, have been utilized to evaluate the role of necroptosis in different diseases, mostly using murine models [2,54]. As a model of acute liver injury, several groups focused on acetaminophen-induced hepatic injury (AIHI) in mice, but the results they obtained were conflicting [2,3,18,57,58,[61][62][63][64][65][66][67][68]. Indeed, the involvement of necroptosis in AIHI is still questionable, and it is still not clear whether RIPK1 or RIPK3 inhibition may have a protective role in this setting [18].…”

Section: Overview On Necroptosis In Liver Diseasementioning

confidence: 99%

Necroptosis in Cholangiocarcinoma

Sarcognato

Jong

Fabris

et al. 2020

Cells

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Necroptosis is a type of regulated cell death that is increasingly being recognized as a relevant pathway in different pathological conditions. Necroptosis can occur in response to multiple stimuli, is triggered by the activation of death receptors, and is regulated by receptor-interacting protein kinases 1 and 3 and mixed-lineage kinase domain-like, which form a regulatory complex called the necrosome. Accumulating evidence suggests that necroptosis plays a complex role in cancer, which is likely context-dependent and can vary among different types of neoplasms. Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis and, as a pro-inflammatory death type, it may inhibit tumor progression by releasing damage-associated molecular patterns to elicit robust cross-priming of anti-tumor CD8+ T cells. The development of therapeutic strategies triggering necroptosis shows great potential for anti-cancer therapy. In this review, we summarize the current knowledge on necroptosis and its role in liver biliary neoplasms, underlying the potential of targeting necroptosis components for cancer treatment.Cells 2020, 9, 982 2 of 18 (RIPK3) and mixed lineage kinase domain-like (MLKL) [4]. Therefore, necroptosis is an alternative mode of CD when the caspase-8-dependent apoptotic pathway is blocked. It is now well-established that various stimuli can initiate necroptosis, including intra-and extracellular factors, such as tumor necrosis factor α (TNFα) and reactive oxygen species (ROS) [5].A hallmark of cancer is the ability of malignant cells to evade apoptosis. Therefore, the induction of necroptosis could be an alternative strategy for killing cancer cells. Several therapeutics able to affect the necroptotic cascade have recently been developed, and a few of them are already in phase 1 trials for the treatment of inflammatory diseases. Moreover, necroptosis modulation is becoming the target of several new anti-cancer strategies. In fact, it has been demonstrated that apoptosis-resistant tumors respond to necroptosis, and that necroptosis can create an immunogenic microenvironment that enhances tumor clearance [6]. These aspects will be further discussed in the following chapters.Herein, we will discuss the general aspects of necroptosis and what is currently known on its involvement in cholangiocarcinoma (CCA), in order to provide perspectives for future studies in this relatively new field. Overview on Types of Cell DeathIn 2005, the Nomenclature Committee on Cell Death (NCCD) defined the first CD classification purely based on morphological criteria. This classification included three major forms of CD: types I, II, and III [7]. Type I CD, termed apoptosis, exhibits cell shrinkage, membrane blebbing, DNA fragmentation, chromatin condensation, and the formation of apoptotic bodies. Apoptosis is a form of RCD and responds to two different death signals: damage from inside the cell, such as DNA damage, which elicits an intrinsic pathway, and extracellular stimuli, such as TNFα and the Fas ligand, ...

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“…The liver histology was independently scored by two experienced pathologists using the Histology Activity Index-(HAI-) Knodell score. Image-Pro Plus 6.0 was used for quantitative analysis of histology and immunohistochemistry [28].…”

Section: Methodsmentioning

confidence: 99%

Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury

Tang

Chen

et al. 2020

BioMed Research International

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Objectives. Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. Methods. eIF2α phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells. Results. Carbon tetrachloride (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. Conclusions. eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.

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Phosphorylation of eIF2α mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury

Cited by 26 publications

References 43 publications

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells

Necroptosis in Cholangiocarcinoma

Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury

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