2013 Fiscal Year Final Research Report
A study on restroration of glucocorticoid sensitivity by regulating SR protein
| Project/Area Number |
24658266
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Single-year Grants |
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| Research Field |
Clinical veterinary science
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| Research Institution | Tokyo University of Agriculture and Technology |
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Principal Investigator |
TANAKA AKANE 東京農工大学, (連合)農学研究科(研究院), 教授 (80418673)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUDA Akira 国立大学法人東京農工大学, 農学研究院, 研究員 (90613969)
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| Project Period (FY) |
2012-04-01 – 2014-03-31
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| Keywords | 治療 / 薬剤反応性 / リンパ腫・白血病 / アレルギー / 免疫学 |
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| Research Abstract |
Glucocorticoid (GC) resistance loses therapeutic options for patients with hematopoietic malignancies. Here we present the novel strategy to overcome GC resistance by modulating splicing regulation of GC receptors (GR) in acute lymphoblastic leukemia (ALL). Dexamethasone exhibited its effects on GC resistant ALL cells when it was administered with a NF-kappaB inhibitor. NF-kappaB inhibition reduced PU.1 and serine-arginine-rich (SR) protein p30c, leading to the increase in a functional isoform but not a dominant negative isoform of GR. PU.1 silencing upregulated total GR pre-mRNA expression, though SRp30c silencing elevated the functional GR. Blocking of the SRp30c binding site in GR pre-mRNA with complementary oligonucleotide restored GC resistance in vivo. We provide the first evidence that NF-kappaB activation induces GC resistance by promoting GR splicing with SRp30c, and blocking of SRp30c binding to GR pre-mRNA accelerates the GC sensitivity by inducing the functional GR.
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[Journal Article] Nuclear factor-ĸB plays a critical role in both intrinsic and acquired resistance against endocrine therapy in human breast cancer cells2014
Author(s)
Oida K, Matsuda A, Jung K, Xia Y, Jang H, Amagai Y, Ahn G, Nishikawa S, Ishizaka S, Jensen-Jarolim E, Matsuda H, Tanaka A
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Journal Title
Sci. Rep
Volume: 17
Pages: 4057
DOI
Peer Reviewed
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[Journal Article] A molecular targeting against nuclear factor-κB, as a chemotherapeutic approach for human malignant mesothelioma2014
Author(s)
Nishikawa S, Tanaka A, Matsuda A, Oida K, Jang H, Jung K, Amagai Y, Ahn G, Okamoto N, Ishizaka S, Matsuda H
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Journal Title
Cancer Med
Volume: 3
Pages: 416-425
DOI
Peer Reviewed
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