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  1. Article ; Online: In lysate

    Akiyama, Yasutoshi / Tomioka, Yoshihisa / Abe, Takaaki / Anderson, Paul / Ivanov, Pavel

    RNA biology

    2021  Volume 18, Issue 12, Page(s) 2546–2555

    Abstract: Under adverse conditions, tRNAs are processed into fragments called tRNA-derived stress-induced RNAs (tiRNAs) by stress-responsive ribonucleases (RNases) such as angiogenin (ANG). Recent studies have reported several biological functions of synthetic ... ...

    Abstract Under adverse conditions, tRNAs are processed into fragments called tRNA-derived stress-induced RNAs (tiRNAs) by stress-responsive ribonucleases (RNases) such as angiogenin (ANG). Recent studies have reported several biological functions of synthetic tiRNAs lacking post-transcriptional modifications found on endogenous tiRNAs. Here we describe a simple and reproducible method to efficiently isolate ANG-cleaved tiRNAs from endogenous tRNAs. Using this
    MeSH term(s) Angiogenesis Inducing Agents/metabolism ; Humans ; RNA Processing, Post-Transcriptional ; RNA, Transfer/genetics ; RNA, Transfer/metabolism ; Ribonuclease, Pancreatic/genetics ; Ribonuclease, Pancreatic/metabolism ; Tumor Cells, Cultured
    Chemical Substances Angiogenesis Inducing Agents ; RNA, Transfer (9014-25-9) ; angiogenin (EC 3.1.27.-) ; Ribonuclease, Pancreatic (EC 3.1.27.5)
    Language English
    Publishing date 2021-06-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2159587-2
    ISSN 1555-8584 ; 1555-8584
    ISSN (online) 1555-8584
    ISSN 1555-8584
    DOI 10.1080/15476286.2021.1930758
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: RTCB Complex Regulates Stress-Induced tRNA Cleavage.

    Akiyama, Yasutoshi / Takenaka, Yoshika / Kasahara, Tomoko / Abe, Takaaki / Tomioka, Yoshihisa / Ivanov, Pavel

    International journal of molecular sciences

    2022  Volume 23, Issue 21

    Abstract: Under stress conditions, transfer RNAs (tRNAs) are cleaved by stress-responsive RNases such as angiogenin, generating tRNA-derived RNAs called tiRNAs. As tiRNAs contribute to cytoprotection through inhibition of translation and prevention of apoptosis, ... ...

    Abstract Under stress conditions, transfer RNAs (tRNAs) are cleaved by stress-responsive RNases such as angiogenin, generating tRNA-derived RNAs called tiRNAs. As tiRNAs contribute to cytoprotection through inhibition of translation and prevention of apoptosis, the regulation of tiRNA production is critical for cellular stress response. Here, we show that RTCB ligase complex (RTCB-LC), an RNA ligase complex involved in endoplasmic reticulum (ER) stress response and precursor tRNA splicing, negatively regulates stress-induced tiRNA production. Knockdown of RTCB significantly increased stress-induced tiRNA production, suggesting that RTCB-LC negatively regulates tiRNA production. Gel-purified tiRNAs were repaired to full-length tRNAs by RtcB in vitro, suggesting that RTCB-LC can generate full length tRNAs from tiRNAs. As RTCB-LC is inhibited under oxidative stress, we further investigated whether tiRNA production is promoted through the inhibition of RTCB-LC under oxidative stress. Although hydrogen peroxide (H
    MeSH term(s) Hydrogen Peroxide/pharmacology ; RNA, Transfer/metabolism ; Oxidative Stress ; RNA Splicing ; Ligases/genetics
    Chemical Substances Hydrogen Peroxide (BBX060AN9V) ; RNA, Transfer (9014-25-9) ; Ligases (EC 6.-)
    Language English
    Publishing date 2022-10-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms232113100
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice.

    Nakai, Taku / Iwamura, Yuma / Kato, Koichiro / Hirano, Ikuo / Matsumoto, Yotaro / Tomioka, Yoshihisa / Yamamoto, Masayuki / Suzuki, Norio

    Blood advances

    2023  Volume 7, Issue 15, Page(s) 3793–3805

    Abstract: The erythroid growth factor erythropoietin (EPO) is mainly produced by the kidneys in adult mammals and induces expansion of erythroid cells and iron use for hemoglobin synthesis. The liver also produces EPO at a lower level than the kidneys. Renal and ... ...

    Abstract The erythroid growth factor erythropoietin (EPO) is mainly produced by the kidneys in adult mammals and induces expansion of erythroid cells and iron use for hemoglobin synthesis. The liver also produces EPO at a lower level than the kidneys. Renal and hepatic EPO production is fundamentally regulated by hypoxia-inducible transcription factors (HIFs) in a hypoxia/anemia-inducible manner. Recently, small compounds that activate HIFs and EPO production in the kidneys by inhibiting HIF-prolyl hydroxylases (HIF-PHIs) have been launched to treat EPO-deficiency anemia in patients with kidney disease. However, the roles of the liver in the HIF-PHI-mediated induction of erythropoiesis and iron mobilization remain controversial. Here, to elucidate the liver contributions to the therapeutic effects of HIF-PHIs, genetically modified mouse lines lacking renal EPO-production ability were analyzed. In the mutant mice, HIF-PHI administration marginally increased plasma EPO concentrations and peripheral erythrocytes by inducing hepatic EPO production. The effects of HIF-PHIs on the mobilization of stored iron and on the suppression of hepatic hepcidin, an inhibitory molecule for iron release from iron-storage cells, were not observed in the mutant mice. These findings demonstrate that adequate induction of EPO mainly in the kidney is essential for achieving the full therapeutic effects of HIF-PHIs, which include hepcidin suppression. The data also show that HIF-PHIs directly induce the expression of duodenal genes related to dietary iron intake. Furthermore, hepatic EPO induction is considered to partially contribute to the erythropoietic effects of HIF-PHIs but to be insufficient to compensate for the abundant EPO induction by the kidneys.
    MeSH term(s) Mice ; Animals ; Erythropoiesis ; Hepcidins/genetics ; Pharmaceutical Preparations ; Erythropoietin/pharmacology ; Erythropoietin/genetics ; Erythropoietin/metabolism ; Kidney ; Anemia/drug therapy ; Iron/metabolism ; Hypoxia/metabolism ; Mammals/metabolism
    Chemical Substances Hepcidins ; Pharmaceutical Preparations ; Erythropoietin (11096-26-7) ; Iron (E1UOL152H7)
    Language English
    Publishing date 2023-05-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2023009798
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Chronopharmacology of diuresis via metabolic profiling and key biomarker discovery of the traditional Chinese prescription Ji-Ming-San using tandem mass spectrometry in rat models.

    Hsieh, Cheng-Yang / Tsai, Po-Wei / Tomioka, Yoshihisa / Matsumoto, Yotaro / Akiyama, Yasutoshi / Wang, Ching-Chiung / Tayo, Lemmuel L / Lee, Chia-Jung

    Phytomedicine : international journal of phytotherapy and phytopharmacology

    2023  Volume 124, Page(s) 155260

    Abstract: Background: Ji-Ming-Shan (JMS) is a traditional prescription used for patients with rheumatism, tendons swelling, relief of foot pain, athlete's foot, diuresis, gout. Although many studies have investigated the active compounds in each herb, the ... ...

    Abstract Background: Ji-Ming-Shan (JMS) is a traditional prescription used for patients with rheumatism, tendons swelling, relief of foot pain, athlete's foot, diuresis, gout. Although many studies have investigated the active compounds in each herb, the functional mechanism behind its therapeutic effect remains unclear.
    Study design: Metabolic cages for sample collection. The serum components obtained from the experimental animals were analyzed using LC-MS/MS. Furthermore, cross-analysis using the software MetaboAnalyst and Venn diagrams were used to investigate chronopharmacology of JMS in the animal models.
    Purpose: The aim of this study is to analyze the diuretic effects of JMS and to explore their chronopharmacology involved in organ regulation through four-quarter periods from serum samples of rat models.
    Methods: Metabolic cages were used for collecting the urine samples and PocketChem UA PU-4010, Fuji DRI-CHEM 800 were used to examine the urine biochemical parameters. The serum components were identified through ultra-performance liquid chromatography-quadrupole time-of-flight (UPLC-Q-TOF) with a new developed method. Cross analysis, Venn diagram, MetaboAnalyst were used to investigate the key biomarker and major metabolism route with the oral administration of the drug.
    Result: JMS significantly changed the 6 h urine volume with no observed kidney toxicity. Urine pH value ranges from 7.0 to 7.5. The chronopharmacology of JMS diuresis activity were 0-6 and 6-12 groups. UPLC-Q-TOF analyses identified 243 metabolites which were determined in positive mode and negative mode respectively. With cross analysis in the Venn diagram, one key biomarker naringenin-7-O-glucoside has been identified. Major metabolic pathways such as 1: Glycerophospholipid metabolism, 2: Primary bile acid biosynthesis, 3: Sphingolipid metabolism, 4: Riboflavin metabolism, 5: Linoleic acid metabolism, 6: Butanoate metabolism.
    Conclusion: JMS significantly changed the urine output of animals in the 0-6 and 6-12 groups. No change in urine pH was observed and also kidney toxicity. A new UPLC-Q-TOF method was developed for the detection of the metabolites of JMS after oral administration. The cross analysis with Venn diagram and identified the key biomarker of JMS namely naringenin-7-O-glucoside. The results showed that six major pathways are involved in the gastrointestinal system and the liver. This study demonstrated the capability of JMS prescription in the regulation of diuresis and identified a key biomarker that is responsible for its therapeutic effect.
    MeSH term(s) Rats ; Humans ; Animals ; Tandem Mass Spectrometry/methods ; Rats, Sprague-Dawley ; Chromatography, Liquid ; Chromatography, High Pressure Liquid/methods ; Drugs, Chinese Herbal/analysis ; Diuresis ; Biomarkers ; China
    Chemical Substances Drugs, Chinese Herbal ; Biomarkers
    Language English
    Publishing date 2023-12-06
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1205240-1
    ISSN 1618-095X ; 0944-7113
    ISSN (online) 1618-095X
    ISSN 0944-7113
    DOI 10.1016/j.phymed.2023.155260
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: In lysate RNA digestion provides insights into the angiogenin’s specificity towards transfer RNAs

    Akiyama, Yasutoshi / Tomioka, Yoshihisa / Abe, Takaaki / Anderson, Paul / Ivanov, Pavel

    RNA biology. 2021 Dec. 02, v. 18, no. 12

    2021  

    Abstract: Under adverse conditions, tRNAs are processed into fragments called tRNA-derived stress-induced RNAs (tiRNAs) by stress-responsive ribonucleases (RNases) such as angiogenin (ANG). Recent studies have reported several biological functions of synthetic ... ...

    Abstract Under adverse conditions, tRNAs are processed into fragments called tRNA-derived stress-induced RNAs (tiRNAs) by stress-responsive ribonucleases (RNases) such as angiogenin (ANG). Recent studies have reported several biological functions of synthetic tiRNAs lacking post-transcriptional modifications found on endogenous tiRNAs. Here we describe a simple and reproducible method to efficiently isolate ANG-cleaved tiRNAs from endogenous tRNAs. Using this in vitro method, more than 50% of mature tRNAs are cleaved into tiRNAs which can be enriched using complementary oligonucleotides. Using this method, the yield of isolated endogenous 5ʹ-tiRNAᴳˡʸ⁻ᴳCC was increased about fivefold compared to when tiRNAs were obtained by cellular treatment of ANG. Although the non-specific ribonuclease activity of ANG is much lower than that of RNase A, we show that ANG cleaves physiologically folded tRNAs as efficiently as bovine RNase A. These results suggest that ANG is highly specialized to cleave physiologically folded tRNAs. Our method will greatly facilitate the analysis of endogenous tiRNAs to elucidate the physiological functions of ANG.
    Keywords angiogenin ; cattle ; digestion ; oligonucleotides ; ribonucleases
    Language English
    Dates of publication 2021-1202
    Size p. 2546-2555.
    Publishing place Taylor & Francis
    Document type Article
    ISSN 1555-8584
    DOI 10.1080/15476286.2021.1930758
    Database NAL-Catalogue (AGRICOLA)

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  6. Article: Altered binding avidities and improved growth inhibitory effects of novel anti-HER3 mAb against human cancers in the presence of HER1-or HER2-targeted drugs

    Okita, Kouki / Imai, Kazuki / Kato, Kazunori / Sugiura, Reiko / Endo, Yuichi / Masuko, Kazue / Tomioka, Yoshihisa / Masuko, Takashi

    Biochemical and biophysical research communications. 2021 Oct. 22, v. 576

    2021  

    Abstract: HER1-and HER2-targeted drugs are effective in cancer therapy, especially against lung, breast and colon malignancies; however, resistance of cancer cells to HER1-and HER2-targeted therapies is becoming a serious problem. The avidity/affinity constant (KA) ...

    Abstract HER1-and HER2-targeted drugs are effective in cancer therapy, especially against lung, breast and colon malignancies; however, resistance of cancer cells to HER1-and HER2-targeted therapies is becoming a serious problem. The avidity/affinity constant (KA) and growth inhibitory effect of anti-HER3 rat monoclonal antibodies (mAb, Ab1∼Ab6) in the presence of therapeutic mAb or low-molecular-weight inhibitors against HER family proteins were analyzed by flow cytometry-based Scatchard plots (Splot) and cell proliferation assay. The KA of Ab3 and Ab6, but not Ab1 or Ab4, split into dual (high and low) modes of KA, and Ab6 exhibited greater anti-proliferative effects against LS-174T colon cancer cells in the presence of Pertuzumab (anti-HER2 mAb). A high KA by Ab6 and Ab6-mediated increased growth inhibition were observed against NCI–H1838 lung or BT474 breast cancer cells, respectively, in the presence of Panitumumab (anti-HER1 mAb) or Perutuzumab. A high KA by Ab6 and Ab6-mediated increased anti-proliferative effects against NCI–H1838 or BT474 were also respectively observed in the presence of Erlotinib (HER1 inhibitor) or Lapatinib (HER1/HER2 inhibitor). In HER1-knockout (KO) NCI–H1838, the reactivity and KA of Ab4 increased compared with in parent NCI–H1838. In HER1-KO or HER3-KO SW1116 colon cancer cells, dual modes of KA with Pertuzumab were noted, and the combination Ab6 and Pertuzumab promoted growth inhibition of HER1-KO, but not of parent SW1116.
    Keywords breast neoplasms ; breasts ; cancer therapy ; cell proliferation ; colon ; colorectal neoplasms ; growth retardation ; humans ; lungs ; rats ; research
    Language English
    Dates of publication 2021-1022
    Size p. 59-65.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 205723-2
    ISSN 0006-291X ; 0006-291X
    ISSN (online) 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2021.08.091
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  7. Article: Selective Cleavage at CCA Ends and Anticodon Loops of tRNAs by Stress-Induced RNases.

    Akiyama, Yasutoshi / Lyons, Shawn M / Fay, Marta M / Tomioka, Yoshihisa / Abe, Takaaki / Anderson, Paul J / Ivanov, Pavel

    Frontiers in molecular biosciences

    2022  Volume 9, Page(s) 791094

    Abstract: Stress-induced tRNA cleavage has been implicated in various cellular processes, where tRNA fragments play diverse regulatory roles. Angiogenin (ANG), a member of the RNase A superfamily, induces cleavage of tRNAs resulting in the formation of tRNA- ... ...

    Abstract Stress-induced tRNA cleavage has been implicated in various cellular processes, where tRNA fragments play diverse regulatory roles. Angiogenin (ANG), a member of the RNase A superfamily, induces cleavage of tRNAs resulting in the formation of tRNA-derived stress-induced RNAs (tiRNAs) that contribute to translational reprogramming aiming at cell survival. In addition to cleaving tRNA anticodon loops, ANG has been shown to cleave 3'-CCA termini of tRNAs
    Language English
    Publishing date 2022-03-01
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2814330-9
    ISSN 2296-889X
    ISSN 2296-889X
    DOI 10.3389/fmolb.2022.791094
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Dual-targeting therapy against HER3/MET in human colorectal cancers.

    Yamasaki, Akitaka / Miyake, Rikuto / Hara, Yuta / Okuno, Hideki / Imaida, Takuya / Okita, Kouki / Okazaki, Shogo / Akiyama, Yasutoshi / Hirotani, Kenji / Endo, Yuichi / Masuko, Kazue / Masuko, Takashi / Tomioka, Yoshihisa

    Cancer medicine

    2023  Volume 12, Issue 8, Page(s) 9684–9696

    Abstract: Background: Colorectal cancer (CRC) is the most common malignancy in the world, and novel molecular targeted therapies for CRC have been vigorously pursued. We searched for novel combination therapies based on the expression patterns of membrane ... ...

    Abstract Background: Colorectal cancer (CRC) is the most common malignancy in the world, and novel molecular targeted therapies for CRC have been vigorously pursued. We searched for novel combination therapies based on the expression patterns of membrane proteins in CRC cell lines.
    Results: A positive correlation was observed between the expression of human pidermal growth factor receptor (HER) 3 and mesenchymal-to-epithelial transition factor (MET) on the cell surface of CRC cell lines. The brief stimulation of HER3/MET-high SW1116 CRC cells with both neuregulin-1 (NRG1) and hepatocyte growth factor enhanced ERK phosphorylation and cell proliferation more than each stimulation alone. In addition, a prolonged NRG1 stimulation resulted in the tyrosine phosphorylation of MET. In this context, the Forkhead Box protein M1 (FOXM1)-regulated tyrosine phosphorylation of MET by NRG1 was demonstrated, suggesting the existence of a signaling pathway mediated by FOXM1 upon the NRG1 stimulation. Since the co-expression of HER3 and MET was also demonstrated in in vivo CRC tissues by immunohistochemistry, we investigated whether the co-inhibition of HER3 and MET could be an effective therapy for CRC. We established HER3-and/or MET-KO SW1116 cell lines, and HER3/MET-double KO resulted in the inhibition of in vitro cell proliferation and in vivo tumor growth in nude mice by SW1116 cells. Furthermore, the combination of patritumab, an anti-HER3 fully human mAb, and PHA665752, a MET inhibitor, markedly inhibited in vitro cell proliferation, 3D-colony formation, and in vivo tumor growth in nude mice by SW1116 cells CONCLUSION: The dual targeting of HER3/MET has potential as CRC therapy.
    MeSH term(s) Humans ; Animals ; Mice ; Mice, Nude ; Cell Line, Tumor ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Signal Transduction ; Cell Proliferation ; Tyrosine
    Chemical Substances Tyrosine (42HK56048U)
    Language English
    Publishing date 2023-02-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2659751-2
    ISSN 2045-7634 ; 2045-7634
    ISSN (online) 2045-7634
    ISSN 2045-7634
    DOI 10.1002/cam4.5673
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  9. Article ; Online: Urinary growth differentiation factor 15 predicts renal function decline in diabetic kidney disease.

    Oshita, Toma / Watanabe, Shun / Toyohara, Takafumi / Kujirai, Ryota / Kikuchi, Koichi / Suzuki, Takehiro / Suzuki, Chitose / Matsumoto, Yotaro / Wada, Jun / Tomioka, Yoshihisa / Tanaka, Tetsuhiro / Abe, Takaaki

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 12508

    Abstract: Sensitive biomarkers can enhance the diagnosis, prognosis, and surveillance of chronic kidney disease (CKD), such as diabetic kidney disease (DKD). Plasma growth differentiation factor 15 (GDF15) levels are a novel biomarker for mitochondria-associated ... ...

    Abstract Sensitive biomarkers can enhance the diagnosis, prognosis, and surveillance of chronic kidney disease (CKD), such as diabetic kidney disease (DKD). Plasma growth differentiation factor 15 (GDF15) levels are a novel biomarker for mitochondria-associated diseases; however, it may not be a useful indicator for CKD as its levels increase with declining renal function. This study explores urinary GDF15's potential as a marker for CKD. The plasma and urinary GDF15 as well as 15 uremic toxins were measured in 103 patients with CKD. The relationship between the urinary GDF15-creatinine ratio and the uremic toxins and other clinical characteristics was investigated. Urinary GDF15-creatinine ratios were less related to renal function and uremic toxin levels compared to plasma GDF15. Additionally, the ratios were significantly higher in patients with CKD patients with diabetes (p = 0.0012) and reduced with statin treatment. In a different retrospective DKD cohort study (U-CARE, n = 342), multiple and logistic regression analyses revealed that the baseline urinary GDF15-creatinine ratios predicted a decline in estimated glomerular filtration rate (eGFR) over 2 years. Compared to the plasma GDF15 level, the urinary GDF15-creatinine ratio is less dependent on renal function and sensitively fluctuates with diabetes and statin treatment. It may serve as a good prognostic marker for renal function decline in patients with DKD similar to the urine albumin-creatinine ratio.
    MeSH term(s) Humans ; Diabetic Nephropathies ; Cohort Studies ; Creatinine/urine ; Growth Differentiation Factor 15 ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Retrospective Studies ; Uremic Toxins ; Disease Progression ; Renal Insufficiency, Chronic/complications ; Glomerular Filtration Rate ; Biomarkers ; Kidney/physiology ; Diabetes Mellitus
    Chemical Substances Creatinine (AYI8EX34EU) ; Growth Differentiation Factor 15 ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Uremic Toxins ; Biomarkers
    Language English
    Publishing date 2023-08-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-39657-7
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  10. Article ; Online: CD98 regulates the phosphorylation of HER2 and a bispecific anti-HER2/CD98 antibody inhibits the growth signal of human breast cancer cells.

    Yamasaki, Akitaka / Maruyama-Takahashi, Kumiko / Nishida, Kento / Okazaki, Shogo / Okita, Kouki / Akiyama, Yasutoshi / Suzuki, Hideaki / Endo, Yuichi / Masuko, Kazue / Masuko, Takashi / Tomioka, Yoshihisa

    Genes to cells : devoted to molecular & cellular mechanisms

    2023  Volume 28, Issue 5, Page(s) 374–382

    Abstract: Human epidermal growth factor receptor (HER) family proteins are currently major targets of therapeutic monoclonal antibodies against various epithelial cancers. However, the resistance of cancer cells to HER family-targeted therapies, which may be ... ...

    Abstract Human epidermal growth factor receptor (HER) family proteins are currently major targets of therapeutic monoclonal antibodies against various epithelial cancers. However, the resistance of cancer cells to HER family-targeted therapies, which may be caused by cancer heterogeneity and persistent HER phosphorylation, often reduces overall therapeutic effects. We herein showed that a newly discovered molecular complex between CD98 and HER2 affected HER function and cancer cell growth. The immunoprecipitation of the HER2 or HER3 protein from lysates of SKBR3 breast cancer (BrCa) cells revealed the HER2-CD98 or HER3-CD98 complex. The knockdown of CD98 by small interfering RNAs inhibited the phosphorylation of HER2 in SKBR3 cells. A bispecific antibody (BsAb) that recognized the HER2 and CD98 proteins was constructed from a humanized anti-HER2 (SER4) IgG and an anti-CD98 (HBJ127) single chain variable fragment, and this BsAb significantly inhibited the cell growth of SKBR3 cells. Prior to the inhibition of AKT phosphorylation, BsAb inhibited the phosphorylation of HER2, however, significant inhibition of HER2 phosphorylation was not observed in anti-HER2 pertuzumab, trastuzumab, SER4 or anti-CD98 HBJ127 in SKBR3 cells. The dual targeting of HER2 and CD98 has potential as a new therapeutic strategy for BrCa.
    MeSH term(s) Humans ; Female ; Breast Neoplasms/pathology ; Receptor, ErbB-2/metabolism ; Trastuzumab/pharmacology ; Trastuzumab/metabolism ; Trastuzumab/therapeutic use ; Antibodies, Monoclonal/metabolism ; Phosphorylation ; Cell Line, Tumor
    Chemical Substances Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK) ; Antibodies, Monoclonal
    Language English
    Publishing date 2023-03-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 1330000-3
    ISSN 1365-2443 ; 1356-9597
    ISSN (online) 1365-2443
    ISSN 1356-9597
    DOI 10.1111/gtc.13016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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