Cell-Nonautonomous ER Stress-Mediated Dysregulation of Immunity by Cancer Cells

Abstract Background Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

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Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras‐Raf‐MAPK signalling

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.16237 ◽

2020 ◽

Author(s):

Yongye Huang ◽

Kexun Yuan ◽

Meifang Tang ◽

Jiaming Yue ◽

Lijun Bao ◽

...

Keyword(s):

Gastric Cancer ◽

Er Stress ◽

Cancer Cells ◽

Human Gastric Cancer ◽

Gastric Cancer Cells ◽

Mapk Signalling

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Targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy

Biology Open ◽

10.1242/bio.053298 ◽

2020 ◽

Vol 9 (11) ◽

pp. bio053298

Author(s):

Jingjing Wu ◽

Youqile Wu ◽

Xuemei Lian

Keyword(s):

Lung Cancer ◽

Protein Expression ◽

Cell Viability ◽

Er Stress ◽

Cancer Cells ◽

Lung Tumor ◽

Lung Cancer Cells ◽

Dependent Manner ◽

Mice Model ◽

Targeted Inhibition

ABSTRACTThis study investigated the pathophysiological role of GRP78 in the survival of lung cancer cells. Lung cancer patient data from public databases were used to analyze the expression of GRP78 and its influence on prognoses. In vivo, GRP78 protein expression was analyzed in an established urethane-induced lung tumor mouse model. In vitro, the effects of targeted inhibition of GRP78 by HA15 in lung cancer cells were assessed, with cell viability analyzed using a CCK-8 assay, cell proliferation using an EdU assay, apoptosis and cell cycle using flow cytometry, subcellular structure using electron microscopy, and relative mRNA and protein expression using RT-PCR, western blotting or immunofluorescence assays. The results showed that GRP78 was highly expressed in the lung tissue of lung cancer mice model or patients, and was associated with a poor prognosis. After inhibition of GRP78 in lung cancer cells by HA15, cell viability was decreased in a dose- and time-dependent manner, proliferation was suppressed and apoptosis promoted. Unfolded protein response signaling pathway proteins were activated, and the autophagy-related proteins and mRNAs were upregulated. Therefore, targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy.

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ER stress compromises VEGFA secretion of pancreatic cancer cells under hypoxic conditions, thereby contributing to tumor hypoxia

HPB ◽

10.1016/j.hpb.2016.01.431 ◽

2016 ◽

Vol 18 ◽

pp. e837

Author(s):

B. Kong ◽

T. Cheng ◽

I. Regel ◽

S. Raulefs ◽

H. Friess ◽

...

Keyword(s):

Pancreatic Cancer ◽

Er Stress ◽

Cancer Cells ◽

Tumor Hypoxia ◽

Hypoxic Conditions ◽

Pancreatic Cancer Cells

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γ-Synuclein is Closely Involved in Autophagy that Protects Colon Cancer Cell from Endoplasmic Reticulum Stress

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210119093327 ◽

2021 ◽

Vol 21 ◽

Author(s):

Qing Ye ◽

Yuanfei Peng ◽

Feng Huang ◽

Jinhu Chen ◽

Yangmei Xu ◽

...

Keyword(s):

Colon Cancer ◽

Western Blot ◽

Er Stress ◽

Cancer Cells ◽

Early Stage ◽

Colon Cancer Cell ◽

Colon Cancer Cells ◽

Rt Pcr ◽

Jnk Pathway ◽

Hct116 Cells

Background: In previous studies, we provided evidence suggesting the involvement of γ-synuclein in growth, invasion, and metastasis of colon cancer cells in vitro and in vivo. Among γ-synuclein downstream genes, the microtubule-associated protein 1 light chain 3 (LC3), an autophagy gene, was screened by gene expression profile chip analysis. Objective: We planned to investigate the functional effects of γ-synuclein on autophagy induced by ER stress in colon cancer cells. Methods: We investigated the functional effects of γ-synuclein on autophagy and apoptosis induced by Thapsigargin (TG), ER stressinducing agent, in colon cancer cell lines using immunofluorescence staining, RT-PCR, western blot, CCK8 test, flow cytometry analysis, and transmission electron microscopy. To further determine how γ-synuclein regulated autophagy and apoptosis, PD98059 (ERK inhibitor), SP600125 (ERK inhibitor), anisomycin (JNK activator), and c-Jun siRNA were used respectively in γ-synuclein siRNA transfected HCT116 cells. Then, autophagy proteins, apoptosis proteins, and pathway proteins were detected by western blot analysis. The expression of autophagy genes was assessed by RT-PCR. Results: Our data showed that ER stress-induced colon cancer cells autophagy mainly in the early stage (0-24h) and apoptosis mainly in the late stage (24-48h). ER stress up-regulated γ-synuclein gene and protein expression in colon cancer cells, accompanied by autophagy. γ-synuclein protected HCT116 cells by enhancing autophagy in the early stage (0-24h) through activation of ERK and JNK pathway and inhibiting apoptosis in the late stage (24-48h) through inhibition of the JNK pathway. γ-synuclein could promote autophagy via the JNK pathway activation of ATG genes, LC3, Beclin 1, and ATG7. γ-synuclein may play a role in the transition between autophagy and apoptosis in our model. Conclusion: Overall, we provided the first experimental evidence to show that γ-synuclein may play an important role in autophagy that protects colon cancer cells from ER stress. Therefore, our data suggest a new molecular mechanism for γ-synuclein-mediated CRC progression.

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Sequencing of Argonaute-bound miRNA/mRNA hybrids reveals regulation of the unfolded protein response by microRNA-320a

10.1101/2021.10.05.463240 ◽

2021 ◽

Author(s):

Christopher J Fields ◽

Lu Li ◽

Nicholas M Hiers ◽

Tianqi Li ◽

Peike Sheng ◽

...

Keyword(s):

Colorectal Cancer ◽

Er Stress ◽

Unfolded Protein Response ◽

Cancer Cells ◽

Rna Polymerase Ii ◽

Mirna Biogenesis ◽

Unfolded Protein ◽

Colorectal Cancer Cells ◽

The Unfolded Protein Response ◽

Protein Response

MicroRNAs (miRNA) are short non-coding RNAs widely implicated in gene regulation. Most metazoan miRNAs utilize the RNase III enzymes Drosha and Dicer for biogenesis. One notable exception is the RNA polymerase II transcription start sites (TSS) miRNAs whose biogenesis does not require Drosha. The functional importance of the TSS-miRNA biogenesis is uncertain. To better understand the function of TSS-miRNAs, we applied a modified Crosslinking, Ligation, and Sequencing of Hybrids on Argonaute (AGO-qCLASH) to identify the targets for TSS-miRNAs in HCT116 colorectal cancer cells with or without DROSHA knockout. We observed that miR-320a hybrids dominate in TSS-miRNA hybrids identified by AGO-qCLASH. Targets for miR-320a are enriched in the eIF2 signaling pathway, a downstream component of the unfolded protein response. Consistently, in miR-320a mimic- and antagomir- transfected cells, differentially expressed genes are enriched in eIF2 signaling. Within the AGO-qCLASH data, we identified the endoplasmic reticulum (ER) chaperone Calnexin as a direct miR-320a target, thus connecting miR-320a to the unfolded protein response. During ER stress, but not amino acid deprivation, miR-320a up-regulates ATF4, a critical transcription factor for resolving ER stress. Our study investigates the targetome of the TSS-miRNAs in colorectal cancer cells and establishes miR-320a as a regulator of unfolded protein response.

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