Isoliquiritigenin Inhibits Gastric Cancer Stemness, Modulates Tumor Microenvironment, and Suppresses Tumor Growth through Glucose-Regulated Protein 78 Downregulation

Lee, Chien-Hsing; Tsai, Hsin–Yi; Chen, Chun-Lin; Chen, Jen-Lung; Lu, Chao-Chun; Fang, Yi‐Ping; Wu, Deng-Chyang; Huang, Yaw‐Bin; Lin, Ming‐Wei

doi:10.3390/biomedicines10061350

Cited by 23 publications

(16 citation statements)

References 49 publications

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“…The quantification of proteins in exosomes contained in a small quantity of patient serum samples will provide a relatively noninvasive method of diagnosing cancer and its prognosis. In addition, quantification of exosomal proteins, such as GRP78, may be indispensable for elucidating the mechanism of cancer progression, because the scenario of this progression is not yet clarified [ 50 , 51 , 52 ]. We strongly believe that the present technique will provide detailed insight into the tumor microenvironment and cell–cell communication and contribute to elucidating the mechanisms of cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Ultrasensitive Detection of GRP78 in Exosomes and Observation of Migration and Proliferation of Cancer Cells by Application of GRP78-Containing Exosomes

Tsurusawa

Iha

Sato

et al. 2022

Cancers

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Cancer cells communicate with each other via exosomes in the tumor microenvironment. However, measuring trace amounts of proteins in exosomes is difficult, and thus the cancer stemness-promoting mechanisms of exosomal proteins have not been elucidated. In the present study, we attempted to quantify trace amounts of 78-kDa glucose-regulated protein (GRP78), which is involved in cancer progression, in exosomes released from cultured gastric cancer cells using an ultrasensitive ELISA combined with thio-NAD cycling. We also evaluated the cancer stemness-promoting effects by the application of high-GRP78-containing exosomes to cultured gastric cancer cells. The ultrasensitive ELISA enabled the detection of GRP78 at a limit of detection of 0.16 pg/mL. The stemness of cancer cultured cells incubated with high-GRP78-containing exosomes obtained from GRP78-overexpressed cells was increased on the basis of both an MTT assay and a wound healing assay. Our results demonstrated that the ultrasensitive ELISA has strong potential to measure trace amounts of proteins in exosomes. Further, exosomes with a high concentration of GRP78 promote the cancer stemness of surrounding cells. The technique for quantifying proteins in exosomes described here will advance our understanding of cancer stemness progression via exosomes.

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Section: Discussionmentioning

confidence: 99%

Ultrasensitive Detection of GRP78 in Exosomes and Observation of Migration and Proliferation of Cancer Cells by Application of GRP78-Containing Exosomes

Tsurusawa

Iha

Sato

et al. 2022

Cancers

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“…The above results showed that targeting genes with inhibitors or antibodies to inhibit CSCs has potential in treating tumors, which is also applicable in GC. Chien-Hsing Lee et al found that liquiritigenin inhibited the stem cell-like characteristics of GC by down-regulating the expression of glucose-regulated protein 78 and inhibiting the growth of GC [ 54 ]. Therefore, inhibiting GC stemness by inhibiting the expression of GCSCs-related genes is also a method for treating GC.…”

Section: The Role Of Protein-encoding Genes In Gcscsmentioning

confidence: 99%

Targeting Gastric Cancer Stem Cells to Enhance Treatment Response

Rao

Zhang

Luo

et al. 2022

Cells

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Gastric cancer (GC) was the fourth deadliest cancer in the world in 2020, and about 770,000 people died from GC that year. The death of patients with GC is mainly caused by the metastasis, recurrence, and chemotherapy resistance of GC cells. The cancer stem cell theory defines cancer stem cells (CSCs) as a key factor in the metastasis, recurrence, and chemotherapy resistance of cancer. It considers targeting gastric cancer stem cells (GCSCs) to be an effective method for the treatment of GC. For GCSCs, genes or noncoding RNAs are important regulatory factors. Many experimental studies have found that some drugs can target the stemness of gastric cancer by regulating these genes or noncoding RNAs, which may bring new directions for the clinical treatment of gastric cancer. Therefore, this review mainly discusses related genes or noncoding RNAs in GCSCs and drugs that target its stemness, thereby providing some information for the treatment of GC.

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“…Glucose-regulated protein 78 (GRP78) is involved in various aspects of cancer, such as invasion and metastasis [ 1 ], and GRP78 inhibitors are now considered potential cancer therapy targets [ 2 ]. In the tumor microenvironment, GRP78 contained in exosomes, transport vesicles of about 100-nm in size, is released from cancer cells [ 3 ], where it affects the surrounding cells and induces cancer malignancy [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Gastric Cancer Cell-Derived Exosomal GRP78 Enhances Angiogenesis upon Stimulation of Vascular Endothelial Cells

Iha

Sato

Tsai

et al. 2022

CIMB

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Exosomes containing glucose-regulated protein 78 (GRP78) are involved in cancer malignancy. GRP78 is thought to promote the tumor microenvironment, leading to angiogenesis. No direct evidence for this role has been reported, however, mainly because of difficulties in accurately measuring the GRP78 concentration in the exosomes. Recently, exosomal GRP78 concentrations were successfully measured using an ultrasensitive ELISA. In the present study, GRP78 concentrations in exosomes collected from gastric cancer AGS cells with overexpression of GRP78 (OE), knockdown of GRP78 (KD), or mock GRP78 (mock) were quantified. These three types of exosomes were then incubated with vascular endothelial cells to examine their effects on endothelial cell angiogenesis. Based on the results of a tube formation assay, GRP78-OE exosomes accelerated angiogenesis compared with GRP78-KD or GRP78-mock exosomes. To investigate the mechanisms underlying this effect, we examined the Ser473 phosphorylation state ratio of AKT, which is involved in the angiogenesis process, and found that AKT phosphorylation was increased by GRP78-OE exosome application to the endothelial cells. An MTT assay showed that GRP78-OE exosome treatment increased the proliferation rate of endothelial cells, and a wound healing assay showed that this treatment increased the migration capacity of the endothelial cells. These findings demonstrated that GRP78-containing exosomes promote the tumor microenvironment and induce angiogenesis.

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Isoliquiritigenin Inhibits Gastric Cancer Stemness, Modulates Tumor Microenvironment, and Suppresses Tumor Growth through Glucose-Regulated Protein 78 Downregulation

Cited by 23 publications

References 49 publications

Ultrasensitive Detection of GRP78 in Exosomes and Observation of Migration and Proliferation of Cancer Cells by Application of GRP78-Containing Exosomes

Ultrasensitive Detection of GRP78 in Exosomes and Observation of Migration and Proliferation of Cancer Cells by Application of GRP78-Containing Exosomes

Targeting Gastric Cancer Stem Cells to Enhance Treatment Response

Gastric Cancer Cell-Derived Exosomal GRP78 Enhances Angiogenesis upon Stimulation of Vascular Endothelial Cells

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