Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer.
Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer.
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DOI：
10.3390/cancers10040095
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发表时间：
2018-03-29
期刊：
影响因子：
5.2
通讯作者：
Kahn M
中科院分区：
文献类型：
--
作者：
Manegold P;Lai KKY;Wu Y;Teo JL;Lenz HJ;Genyk YS;Pandol SJ;Wu K;Lin DP;Chen Y;Nguyen C;Zhao Y;Kahn M
背景资料：尽管已知典型的Wnt信号传导促进胰腺导管腺癌（PDAC）（主要由突变型K-Ras驱动的癌症）中的肿瘤发生，但Wnt效应子β-连环蛋白调节这种肿瘤发生的详细分子机制在很大程度上是未知的。我们以前已经证明，β-连环蛋白对Kat 3转录辅激活因子环AMP反应元件结合蛋白结合蛋白（CBP）的差异使用超过其高度同源的辅激活因子p300，增加了自我更新，并抑制了其他类型癌症的分化。目的/方法：为了研究PDAC中Wnt介导的致癌作用，我们使用了我们实验室鉴定并广泛表征的特异性小分子CBP/β-连环蛋白拮抗剂ICG-001，以检查其在人胰腺癌细胞以及原位小鼠模型和人患者来源的PDAC异种移植（PDX）模型中的作用。结果/结论：我们首次报道了K-Ras激活增加了胰腺癌中CBP/β-catenin相互作用;并且CBP/β-catenin相互作用的ICG-001特异性拮抗作用使胰腺癌细胞和肿瘤对吉西他滨治疗敏感。这些作用与let-7a microRNA表达的增加、K-Ras和生存素的抑制以及耐药癌症干细胞/肿瘤起始细胞的消除有关。
Background: Although canonical Wnt signaling is known to promote tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), a cancer driven principally by mutant K-Ras, the detailed molecular mechanisms by which the Wnt effector β-catenin regulates such tumorigenesis are largely unknown. We have previously demonstrated that β-catenin’s differential usage of the Kat3 transcriptional coactivator cyclic AMP-response element binding protein-binding protein (CBP) over its highly homologous coactivator p300 increases self-renewal and suppresses differentiation in other types of cancer. Aim/methods: To investigate Wnt-mediated carcinogenesis in PDAC, we have used the specific small molecule CBP/β-catenin antagonist, ICG-001, which our lab identified and has extensively characterized, to examine its effects in human pancreatic cancer cells and in both an orthotopic mouse model and a human patient-derived xenograft (PDX) model of PDAC. Results/conclusion: We report for the first time that K-Ras activation increases the CBP/β-catenin interaction in pancreatic cancer; and that ICG-001 specific antagonism of the CBP/β-catenin interaction sensitizes pancreatic cancer cells and tumors to gemcitabine treatment. These effects were associated with increases in the expression of let-7a microRNA; suppression of K-Ras and survivin; and the elimination of drug-resistant cancer stem/tumor-initiating cells.
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影响因子：
8
作者：
Kerkhoff, E;Houben, R;Rapp, UR
通讯作者：
Rapp, UR
影响因子：
3.7
作者：
Pasca di Magliano M;Biankin AV;Heiser PW;Cano DA;Gutierrez PJ;Deramaudt T;Segara D;Dawson AC;Kench JG;Henshall SM;Sutherland RL;Dlugosz A;Rustgi AK;Hebrok M
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Hebrok M
影响因子：
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作者：
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通讯作者：
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影响因子：
13.8
作者：
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Der, Channing J.
大黄素对胰腺癌中吉西他滨作用的增强与生存素抑制有关
影响因子：
5.8
作者：
Guo, Qingqu;Chen, Ying;Wu, Yulian
通讯作者：
Wu, Yulian