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PMC12514566 | AGS and AGS-EBV cells were subjected to hypoxia for 24 h, and the expression levels of phosphorylated AKT (p-AKT) at Ser473 and Thr308 were assessed by Western blot. ( | [
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PMC12514566 | AGS and AGS-EBV cells were cultured under normoxic or hypoxic conditions for 24 h, followed by RT-qPCR to measure the relative expression levels of HIF-1α. | [
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PMC12514566 | Data are presented as mean ± SD, with statistical significance indicated (∗p < 0.05, ∗∗∗∗p < 0.0001). | [] |
PMC12514566 | Beyond its effect on the proliferation of EBVaGC cells, we investigated the impact of 2-DG on the EBV life cycle within these cells. | [
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"text": "EBVaGC"
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PMC12514566 | Western blot analysis was performed to assess the expression of EBV lytic proteins, including BZLF1 and BMRF1 in AGS-EBV and SNU719 cell lines treated with 2-DG under hypoxic conditions. | [
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PMC12514566 | Fig. 6 revealed that hypoxia induced the expression of these lytic proteins, promoting EBV lytic reactivation. | [] |
PMC12514566 | However, treatment with 2-DG significantly downregulated the expression of BZLF1, BMRF1 under hypoxic conditions. | [] |
PMC12514566 | These findings suggest that glycolysis is essential for hypoxia-induced EBV lytic reactivation, highlighting the critical role of metabolic pathways in regulating the EBV life cycle within EBVaGC cells. | [] |
PMC12514566 | Fig. 62-DG inhibits hypoxia-induced EBV lytic reactivation in EBVaGC cell lines. | [] |
PMC12514566 | Western blot analysis of EBV lytic proteins Zta (BZLF1) and BMRF1 in AGS-EBV and SNU719 cells under normoxic or hypoxic conditions, with or without 2-DG treatment. | [
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PMC12514566 | Fig. 6 2-DG inhibits hypoxia-induced EBV lytic reactivation in EBVaGC cell lines. | [] |
PMC12514566 | Western blot analysis of EBV lytic proteins Zta (BZLF1) and BMRF1 in AGS-EBV and SNU719 cells under normoxic or hypoxic conditions, with or without 2-DG treatment. | [
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PMC12514566 | Our results demonstrate that 2-DG effectively inhibits cell proliferation in both EBV-infected and uninfected gastric carcinoma cells, with EBVaGC cells showing greater sensitivity, particularly under hypoxic conditions. | [
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"text": "EBVaGC"
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PMC12514566 | This heightened sensitivity in EBVaGC cells was associated with increased glycolytic gene expression, primarily through upregulate HIF-1α mRNA-dependent mechanisms. | [
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PMC12514566 | In addition to inhibiting cell proliferation, 2-DG treatment also inhibited EBV lytic reactivation in EBVaGC cells under hypoxia. | [
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PMC12514566 | This study provides significant insights into the differential effects of the glycolysis inhibitor 2-DG on EBVaGC and EBVnGC and highlights the therapeutic potential of glycolysis inhibition in EBVaGC. | [
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PMC12514566 | Our study represents that the glycolysis inhibitor 2-DG exerts a significantly stronger anti-proliferative effect on EBV-positive AGS cells compared to their EBV-negative counterparts, a differential sensitivity that is further amplified under hypoxic conditions. | [
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PMC12514566 | Currently, there are many studies exploring the impact of EBV infection on glycolysis in tumor cells under normoxic conditions.16, 17, 18 For example, LMP1 enhances glucose metabolism by activating the metabolic enzyme PDHE1α in NPC cells. | [] |
PMC12514566 | However, there is still a lack of research on the effects of EBV infection on glycolysis in tumor cells under hypoxic conditions. | [] |
PMC12514566 | We thought that this phenomenon is not merely a simple additive effect of EBV infection and hypoxia as two independent glycolysis-promoting factors. | [] |
PMC12514566 | Rather, it profoundly reveals that EBV infection fundamentally reshapes the host cell's metabolic architecture. | [] |
PMC12514566 | We propose that EBV infection acts as a potent biological “stressor”, compelling gastric cancer cells to rewire their metabolic network, driving a heightened reliance on glycolytic pathways for carbon skeletons and ultimately pushing the cells into a state of “glycolytic addiction”. | [] |
PMC12514566 | Hypoxia, a key feature of the tumor microenvironment, amplifies the metabolic vulnerability of EBV-positive cells, leading to an extreme dependence on glycolysis. | [] |
PMC12514566 | Perturbation of this metabolic pathway, such as hexokinase inhibition by 2-DG, can trigger cell proliferation arrest and death. | [] |
PMC12514566 | This suggests that 2-DG may have enhanced cytotoxic effects in aggressive, radio/chemotherapy-resistant hypoxic regions of EBVaGC. | [] |
PMC12514566 | Our investigation into the molecular mechanisms of glycolysis upregulation by EBV and hypoxia found that in AGS-EBV cells under hypoxic conditions, the upregulation of glycolysis-related genes is HIF-1α-dependent. | [
{
"end": 115,
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PMC12514566 | Knocking down HIF-1α reversed this effect, while knocking down HIF-2α had no impact. | [] |
PMC12514566 | This aligns with the known functions of HIF-α subtypes, as HIF-1α is the primary regulator of metabolic reprogramming in response to acute hypoxia, directly activating glycolytic enzyme and glucose transporter gene transcription, thus rapidly switching cellular metabolism to glycolysis. | [] |
PMC12514566 | Conversely, although structurally similar to HIF-1α, HIF-2α regulates a vastly different set of target genes, primarily involved in long-term adaptive responses such as angiogenesis, cell fate determination, and iron metabolism, without directly participating in glycolysis pathway regulation. | [] |
PMC12514566 | In fact, previous studies have explicitly stated that HIF-2α does not regulate the glycolytic pathway. | [] |
PMC12514566 | Therefore, our results suggest that EBV infection amplifies the host cell's HIF-1α-mediated hypoxic response, driving a more pronounced glycolytic phenotype, rather than creating a novel signaling pathway. | [] |
PMC12514566 | Our findings indicate that EBV infection enhances HIF-1α activity in gastric cancer cells under hypoxic conditions, a process that doesn't depend on increased protein stability. | [] |
PMC12514566 | To investigate HIF-1α protein stability, we used CoCl2, a well-established hypoxia-mimicking agent. | [] |
PMC12514566 | CoCl2 works by substituting the ferrous iron (Fe) in the active site of prolyl hydroxylase (PHD) enzymes, thereby inhibiting their function. | [] |
PMC12514566 | Since PHDs need oxygen to tag HIF-1α for proteasomal degradation, their inhibition by CoCl2 leads to HIF-1α stabilization and accumulation, effectively mimicking the primary consequence of cellular oxygen deprivation. | [] |
PMC12514566 | We recognize that chemical mimetics don't perfectly replicate the complex environment of physiological hypoxia, which includes broad changes in cellular metabolism and redox status in addition to HIF-1α stabilization. | [] |
PMC12514566 | Despite these differences, the use of CoCl2 remains a valid and targeted approach for specifically investigating the post-translational regulation of HIF-1α stability, which was the precise goal of this experiment. | [] |
PMC12514566 | Under normoxic conditions, where EBV latent proteins like LMP2A activate the PI3K/AKT/mTOR pathway, promoting HIF-1α mRNA translation and a hypoxia-independent increase in HIF-1α protein.27, 28, 29 Our results found that under hypoxic conditions, EBV does not activate PI3K/AKT signaling. | [] |
PMC12514566 | In true hypoxic environments, HIF-1α regulation shifts: hypoxia directly inhibits PHD enzymes, stabilizing and accumulating HIF-1α. | [] |
PMC12514566 | We hypothesize that gastric cancer cells prioritize this potent hypoxic signal over the indirect PI3K/AKT pathway for HIF-1α upregulation, potentially suppressing PI3K/AKT due to energetic stress. | [] |
PMC12514566 | In this context, EBV acts as a "transcriptional amplifier," working with hypoxia-induced protein stability to drive HIF-1α gene expression. | [] |
PMC12514566 | Our study revealed that 2-DG not only inhibited the proliferation of AGS-EBV cells but also significantly suppressed EBV lytic reactivation under hypoxic conditions. | [
{
"end": 76,
"label": "CellLine",
"start": 69,
"text": "AGS-EBV"
}
] |
PMC12514566 | Notably, while hypoxia, through HIF-1α upregulation, can initiate the EBV lytic program, 2-DG remained effective in suppressing lysis even under hypoxic conditions. | [] |
PMC12514566 | This suggests that successful lytic initiation requires not only “transcriptional permission” but also “metabolic permission”. | [] |
PMC12514566 | On one hand, the EBV lytic cycle is highly dependent on metabolic energy, including ATP generation, nucleotide synthesis, and protein translation. | [] |
PMC12514566 | By inhibiting hexokinase, 2-DG cuts off the essential energy and raw material supply required for viral lysis. | [] |
PMC12514566 | This establishes a "metabolic checkpoint," effectively blocking viral replication at the energy level. | [] |
PMC12514566 | On the other hand, 2-DG also interferes with N-linked glycosylation, leading to misfolded viral envelope glycoproteins that accumulate in the endoplasmic reticulum. | [] |
PMC12514566 | This triggers endoplasmic reticulum stress and the unfolded protein response (UPR). | [] |
PMC12514566 | Once activated, the UPR, via mechanisms like eIF2α phosphorylation, globally inhibits protein translation, further preventing viral protein synthesis and the formation of new viral particles. | [] |
PMC12514566 | While lytic induction is explored as a potential "suicide" therapy for EBV-positive cancers, its uncontrolled, spontaneous activation within the tumor microenvironment is often detrimental. | [] |
PMC12514566 | Spontaneous lytic reactivation can create a pro-tumorigenic microenvironment by driving chronic inflammation, promoting angiogenesis through the release of viral factors like BZLF1, and facilitating immune evasion.37, 38, 39, 40 Furthermore, the expression of lytic proteins has been associated with resistance to conventional treatments such as chemotherapy. | [] |
PMC12514566 | Therefore, this approach ingeniously transforms the risk of hypoxia-induced lytic reactivation into a therapeutic advantage. | [] |
PMC12514566 | By allowing 2-DG to exert a dual mechanism—simultaneously targeting host cell metabolism and viral pathogenesis—it strengthens the rationale for using glycolysis inhibitors in the treatment of EBVaGC. | [] |
PMC12514566 | In conclusion, this study demonstrates that the glycolysis inhibitor 2-DG has a stronger inhibitory effect on the proliferation of EBVaGC cells compared to EBVnGC. | [
{
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"text": "EBVaGC"
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{
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"text": "EBVnGC"
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PMC12514566 | Additionally, 2-DG also inhibits EBV lytic reactivation. | [] |
PMC12514566 | These findings underscore the potential of targeting glycolysis as a therapeutic strategy for EBVaGC and reveal the role of EBV-driven glycolytic metabolism. | [] |
PMC12514566 | Yu Du: Writing – review & editing, Writing – original draft, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization. | [] |
PMC12514566 | Wangsheng Zuo: Methodology, Investigation, Data curation, Conceptualization. | [] |
PMC12514566 | Yiting Shao: Methodology, Investigation, Funding acquisition, Data curation, Conceptualization. | [] |
PMC12514566 | Yanying Ji: Methodology, Investigation. | [] |
PMC12514566 | Bojin Su: Methodology, Investigation, Funding acquisition. | [] |
PMC12514566 | Sihong Liang: Methodology, Investigation. | [] |
PMC12514566 | Deyu Wang: Methodology, Investigation. | [] |
PMC12514566 | Bin Li: Methodology, Investigation. | [] |
PMC12514566 | Yujie Feng: Methodology, Investigation. | [] |
PMC12514566 | Liping Gong: Writing – review & editing, Writing – original draft, Funding acquisition, Data curation, Conceptualization. | [] |
PMC12514566 | Jianning Chen: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. | [] |
PMC12514566 | Chunkui Shao: Writing – review & editing, Funding acquisition, Data curation. | [] |
PMC12514566 | During the preparation of this work the author(s) used Google Gemini in order to improve the readability and language of the manuscript. | [] |
PMC12514566 | After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the published article. | [] |
PMC12514566 | This work was supported by the 10.13039/501100001809National Natural Science Foundation of China (82403764, 82202835) and the 10.13039/501100002858China Postdoctoral Science Foundation (2022M713568, 2023M744005), 10.13039/501100021171Guangdong Basic and Applied Basic Research Foundation (2024A1515012426, 2022A1515012555), Guangzhou Science and Technology Project on Fundamental and Applied Basic Research (2023A04J1098). | [] |
PMC12514566 | I have nothing to declare. | [] |
PMC10158546 | Prions are misfolded proteins that accumulate within the brain in association with a rare group of fatal and infectious neurological disorders in humans and animals. | [] |
PMC10158546 | A current challenge to research is a lack of in vitro model systems that are compatible with a wide range of prion strains, reproduce prion toxicity, and are amenable to genetic manipulations. | [] |
PMC10158546 | In an attempt to address this need, here we produced stable cell lines that overexpress different versions of PrP through lentiviral transduction of immortalized human neural progenitor cells (ReN VM). | [
{
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"text": "ReN VM"
}
] |
PMC10158546 | Differentiated cultures made from the neural progenitor cell lines overexpressed PrP within 3D spheroid-like structures of TUBB3 neurons and we observed evidence that PrP modulates formation of these structures, consistent with PrP’s role in neurogenesis. | [] |
PMC10158546 | However, through repeated measurements of amyloid seeding activity in 6-week time course experiments, we failed to observe any evidence of prion replication within the differentiated ReN cultures following challenge with four prion isolates (human sCJD subtypes MM1 and VV2, and rodent adapted scrapie strains RML and 263K). | [
{
"end": 186,
"label": "CellLine",
"start": 183,
"text": "ReN"
}
] |
PMC10158546 | We attributed amyloid seeding activity detected within the cultures to residual inoculum and concluded that PrP overexpression was insufficient to confer permissiveness of ReN cultures to prion infection. | [] |
PMC10158546 | While our ReN cell prion infection model was unsuccessful, additional efforts to develop cellular models of human prion disease are highly warranted. | [
{
"end": 13,
"label": "CellLine",
"start": 10,
"text": "ReN"
}
] |
PMC10158546 | Prion diseases are rare infectious neurological disorders that afflict humans and animals, and are characterized by long pre-clinical incubation periods prior to rapidly progressive neurocognitive decline culminating in death . | [] |
PMC10158546 | The disease causing agent is thought to comprise of misfolded prion proteins (PrP) that are deposited within the brain as plaques in association with neuropathological changes . | [] |
PMC10158546 | Accumulation and spread of prions are mediated by prion replication whereby PrP recruits and converts the host-encoded cellular prion protein (PrP) into the disease-associated conformation . | [] |
PMC10158546 | Prion diseases are diverse with widely varying clinical signs and symptoms encoded by prion strains – defined as infectious isolates with distinct pathological features and are thought to adopt unique 3D conformations of misfolded PrP . | [] |
PMC10158546 | In the laboratory, prion infection is usually achieved through intracerebral inoculation of mice in vivo followed by monitoring of clinical signs over several months to years, faithfully recapitulating the disease seen in humans. | [] |
PMC10158546 | However, in vivo models are long, laborious, costly, and wildtype mice are often infected with synthetic prion isolates that have been adapted to the host through repeated serial passaging . | [] |
PMC10158546 | Synthetic mouse-adapted prion strains are needed because of transmission barriers that are mainly attributed to differences between the amino acid sequence of host-encoded PrP and PrP present in the inoculum . | [] |
PMC10158546 | As such, specialized transgenic mice that express the PrP version of the natural host are often required to overcome transmission barriers and study naturally occurring prion isolates . | [] |
PMC10158546 | Alternatively, bank voles are considered a ‘universal prion acceptor’ because they are susceptible to a wide range of prion isolates including those from humans . | [] |
PMC10158546 | Nonetheless, in vivo mouse and other animal models enable correlation of neuropathological changes with onset of clinical signs and are considered the ‘gold standard’ prion bioassay. | [] |
PMC10158546 | In contrast, development of in vitro models for prion infection has proven much more challenging. | [] |
PMC10158546 | A lack of accessible and useful in vitro models of prion infection has hampered progress towards identifying links between prion replication and toxicity, screening putative therapeutics, and characterizing prion strain diversity. | [] |
PMC10158546 | This is particularly true for human prion isolates that have been notoriously difficult to culture. | [] |
PMC10158546 | Indeed, despite numerous efforts over the years, an immortalized neuron-like cellular model has never successfully replicated naturally occurring human prion isolates . | [] |
PMC10158546 | Certain cell culture systems that propagate prions are often used to examine PrP trafficking, but are mostly limited to isolates of mouse-adapted scrapie and usually do not reproduce prion toxicity . | [] |
PMC10158546 | In contrast to immortalized cell cultures, primary neuronal cultures can be used in the study of acute prion toxicity but do not have the longevity required for prion replication . | [] |
PMC10158546 | Cultured organotypic brain sections have proven to be one of the best in vitro models of prion infection because following several weeks of PrP replication, they reproduce the pathological hallmarks of the disease [14–16]. | [] |
PMC10158546 | However, this system requires a steady supply of live animals, specialized equipment and a high level of technical expertise, reducing accessibility to researchers. | [] |
PMC10158546 | Thus, there is much room for improvement with respect to in vitro models of prion infection. | [] |
PMC10158546 | Cultures derived from differentiated neural progenitor cells have successfully been used to replicate prions in vitro and in some cases have reproduced prion toxicity [17–24]. | [] |
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