Endoplasmic reticulum stress-mediated membrane expression of CRT/ERp57 induces immunogenic apoptosis in drug-resistant endometrial cancer cells

Xu, Qin; Chen, Chuanben; An, Lin; Xie, Ying

doi:10.18632/oncotarget.17678

Cited by 18 publications

(9 citation statements)

References 32 publications

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“…In our experiment, we demonstrate that 3-BrPA may be able to induce the translocation of CRT to the surfaces of tumor cell membranes as a result of ER stress and activate the “eat me” pathway [19, 26, 33]. This “eat me” pathway stimulates the phagocytosis of DCs, which are important antigen presenting cells that initiate T cell-mediated immune responses.…”

Section: Discussionmentioning

confidence: 94%

Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines

Lee

Kang

et al. 2019

J Biomed Sci

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Background Endoplasmic reticulum stress has a profound effect on cancer cell proliferation and survival, and also has the capacity to activate cells of the adaptive immune system. Multimodal treatment methods that utilize and combine conventional cancer therapies with antigen-specific immunotherapies have emerged as promising approaches for the treatment and control of cancer. However, it is not well known whether endoplasmic reticulum stress-inducing agents can influence the efficacy of tumor antigen-targeting vaccines. Methods In the past, we developed a therapeutic human papillomavirus (HPV) DNA vaccine that encodes for calreticulin (CRT) linked to the HPV16 E7 antigen (CRT/E7). In this study, we utilize the CRT/E7 and further encode for an endoplasmic reticulum (ER) stress-inducing agent, 3-bromopyruvate (3-BrPA), in a preclinical model, by harnessing its potential to enhance HPV16 E7-specific CD8+ T cell immune responses as well as antitumor effects against E7-expressing tumors (TC-1 cells). E7-specific CD8+ T cells were added to evaluate the cytotoxicity of luciferase-expressing TC-1 tumor cells treated with 3-BrPA in vitro, as measured with an IVIS Luminescence Imaging System. We also determined the levels of ER stress markers in 3-BrPA-treated TC-1 cells. TC-1 tumor-bearing mice were treated with either 3-BrPA (10 mg/kg, intraperitoneal injection) and/or CRT/E7 DNA vaccine (30 μg/mouse). Results Treatment of E7-expressing TC-1 tumor cells with 3-BrPA induced significantly higher in vitro cytotoxicity and resulted in upregulation of endoplasmic reticulum stress markers (CHOP and GRP78). More importantly, combination treatment of 3-BrPA and the CRT/E7 DNA vaccine led to improved antigen-specific CD8+ T cell immune responses as well as therapeutic antitumor effects in TC-1 tumor-bearing mice. Conclusions Our data indicate that 3-BrPA can enhance therapeutic HPV vaccine potency in generating improved antigen-specific immune responses and antitumor effects. These findings have important implications for future clinical translation and provide novel strategies for the treatment of HPV-associated diseases.

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Section: Discussionmentioning

confidence: 94%

Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines

Lee

Kang

et al. 2019

J Biomed Sci

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“…(Zhou et al, 2018;Jia et al, 2019). Among them, p-PERK, p-elF2α, and CHOP are the main signaling pathways of ERS, and GRP78 is the major marker of ERS (Xu et al, 2017). At the early stage of ERS, GRP7 was separated from PERK, and PERK was dimerized and phosphorylated, resulting in phosphorylation of downstream elF2α, which then alleviated ERS .…”

Section: Discussionmentioning

confidence: 99%

Apigenin Ameliorates Insulin Resistance and Lipid Accumulation by Endoplasmic Reticulum Stress and SREBP-1c/SREBP-2 Pathway in Palmitate-Induced HepG2 Cells and High-Fat Diet–Fed Mice

Guo

Deng

et al. 2021

J Pharmacol Exp Ther

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Insulin resistance (IR) is the common basis of diabetes and cardiovascular diseases, and its development is closely associated with lipid metabolism disorder. Flavonoids have definite chemical defense effects, including anti-inflammatory effects, anti-cancer effects, and anti-mutation effects. However, the function and mechanism of apigenin (AP, a kind of flavonoids) on IR are still unclear. In our study, intracellular fat accumulation model cells and high-fat diet (HFD) fed model mice were established using palmitate (PA) and HFD. Mechanistically, we first demonstrated that AP could notably downregulate sterol regulatory element-binding protein 1c (SREBP-1c), sterol regulatory element-binding protein 2 (SREBP-2), fatty acid synthase (FAS), stearyl-CoA desaturase 1 (SCD-1), and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCOR) in PA-induced hyperlipidemic cells and mice. Functionally, we verified that AP could markedly reduce lipid accumulation in PA-induced hyperlipidemic cells and decrease the body weight, visceral fat weight, IR, and lipid accumulation in HFD-induced hyperlipidemic mice. Besides, we disclosed that PA could significantly downregulate endoplasmic reticulum stress (ERS)-related proteins and inhibit ERS. Furthermore, we proved that AP could reduce blood lipids by inhibiting ERS in PA-induced hyperlipidemic cells. Meanwhile, 4-phenyl butyric acid (4-PBA) (4-PBA, also ERS alleviator), like AP, could significantly reduce blood lipids and alleviate IR inHFD-fed model mice. Therefore, we concluded that AP could substantially improve the disorder of lipid metabolism, and its mechanism might be related to the decrease of SREBP-1c, SREBP-2, and downstream genes, the inhibition of ERS, and the reduction of blood lipids and IR. Significance statementApigenin, a non-toxic and naturally-sourced flavonoid, exerts anti-hyperlipidemic properties in mice and hepatocyte. Our study highlights a new mechanism of apigenin This article has not been copyedited and formatted. The final version may differ from this version.

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“…A TCF-4 tem papel essencial na promoção da apoptose, que é induzida pela fosforilação da eIF2α. [37][38][39] Os resultados deste estudo sugerem que a TCF-4 pode ser responsável pela apoptose do cardiomiócito durante o estresse do RE induzido pela I/R, enquanto o tratamento com a DEX pode diminuir a TCF-4. CHOP, que é membro da família de fatores de transcrição da proteína ligadora do acentuador CCAAT, 40 sendo um marcador clássico da iniciação da apoptose, ou seja, tem papel essencial na apoptose do miocárdio mediada pelo estresse do RE.…”

Section: Discussionunclassified

O Pré-Condicionamento com Dexmedetomidina Reduz a Lesão de Isquemia-Reperfusão do Miocárdio em Ratos, Inibindo a Via PERK

Chen¹,

Cao²,

Chen³

et al. 2021

Arquivos Brasileiros De Cardiologia

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Fundamento: A cardiopatia isquêmica atraiu muito atenção devido às altas taxas de mortalidade, custos do tratamento e a crescente morbidade na população jovem. Estratégias de reperfusão reduziram a mortalidade. Porém, a reperfusão pode levar à morte do cardiomiócito e subsequente dano irreversível ao miocárdio. No momento, não há um tratamento eficiente e direcionado para a lesão de isquemia-reperfusão (I/R). Objetivos: Avaliar se a dexmedetomidina (DEX) tem efeito protetivo na I/R do miocárdio e explorar os possíveis mecanismos por trás dela. Métodos: Corações de ratos foram perfundidos com o sistema de perfusão de Langendorff e aleatoriamente distribuídos em cinco grupos: grupo controle, perfundido com solução de Krebs-Henseleit (K-H) por 205 minutos sem isquemia; e quatro grupos de teste que foram submetidos a 40 minutos de isquemia global e 120 minutos de reperfusão. O Grupo DEX, o grupo ioimbina (IO) e o grupo DEX + IO foram perfundidos com DEX (10 nM), IO (1 μM) ou a combinação de DEX e IO antes da reperfusão, respectivamente. A hemodinâmica cardíaca, o tamanho do infarto do miocárdio e a histologia do miocárdio foram avaliados. A expressão da proteína-78 regulada pela glicose (GRP78), a proteína quinase do retículo endoplasmático (PERK), a PERK fosforilada, o fator de iniciação eucariótico 2α (eIF2α), eIF2α fosforilado, o fator de transcrição 4 (TCF-4) e a proteína homóloga à proteína ligadora do acentuador CCAAT (CHOP) foram avaliados. P<0,05 foi considerado para indicar a diferença estatisticamente significativa. Resultados: O pré-condicionamento com DEX melhorou a função cardíaca nos corações com I/R, reduziu o infarto do miocárdio, a apoptose do miocárdio e a expressão de GRP78, p-PERK, eIF2α, p-eIF2α, TCF-4 e CHOP. Conclusões: O pré-tratamento com DEX reduziu a lesão de I/R no miocárdio ao suprimir a apoptose, o que foi induzido pela via PERK.

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Endoplasmic reticulum stress-mediated membrane expression of CRT/ERp57 induces immunogenic apoptosis in drug-resistant endometrial cancer cells

Cited by 18 publications

References 32 publications

Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines

Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines

Apigenin Ameliorates Insulin Resistance and Lipid Accumulation by Endoplasmic Reticulum Stress and SREBP-1c/SREBP-2 Pathway in Palmitate-Induced HepG2 Cells and High-Fat Diet–Fed Mice

O Pré-Condicionamento com Dexmedetomidina Reduz a Lesão de Isquemia-Reperfusão do Miocárdio em Ratos, Inibindo a Via PERK

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