p38gamma MAPK signaling promotes intestinal tumorigenesis

p38gamma MAPK 信号促进肠道肿瘤发生

基本信息

批准号：
10620848
负责人：
GUAN CHEN
金额：
$ 34.97万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620848
关键词：
APC gene Anti-Inflammatory Agents Attenuated Azoxymethane Carcinoma Cessation of life Clinical Colitis Collaborations Colon Carcinoma Colorectal Cancer Complex DNA Development Effectiveness Epithelial Cells Epithelium Fluorouracil Genetic Genetic Transcription Growth Growth and Development function Human In Vitro Inflammation Inflammatory Interleukin-10 Intestines Knock-out Knockout Mice Leucocytic infiltrate Life MAP Kinase Gene MAPK12 gene Malignant - descriptor Mission Mus Mutant Strains Mice Nuclear Translocation Oncogenic Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Pirfenidone Play Public Health Research Role Severities Signal Transduction Sodium Dextran Sulfate Specimen Spontaneous colitis Suppressor Mutations TCF7L2 gene Testing Therapeutic Therapeutic Intervention Tissues United States National Institutes of Health WNT Signaling Pathway Wild Type Mouse Xenograft procedure antagonist burden of illness c-myc Genes cancer cell chemotherapy cofactor colitis associated cancer colon tumorigenesis cytokine dextran sulfate sodium induced colitis driving force druggable target in vivo inhibitor intestinal epithelium intestinal tumorigenesis member mouse model multicatalytic endopeptidase complex murine colitis novel novel strategies overexpression p38 Mitogen Activated Protein Kinase pharmacologic promoter response targeted cancer therapy targeted treatment tumorigenesis

项目摘要

Colorectal cancer (CRC) is the second leading cause of malignant-associated death in the USA with inflammation as a key driving force for its development, growth, and progression. p38, a member of p38 mitogen-activated protein kinases (p38 MAPK  , and ), is oncogenic, pro-inflammatory, and overexpressed in clinical CRC but the role of epithelial p38 in CRC tumorigenesis has not been tested. - catenin, a critical cofactor of Wnt transcription, is aberrantly activated in 90% of CRC. And yet, -catenin is undruggable and there is thus an urgent need to identify druggable -catenin activators for therapeutic intervention. Here we propose that p38 MAPK in intestinal epithelial cells (IEC) drives CRC tumorigenesis by stimulating oncogenic -catenin phosphorylation. This hypothesis is based on our preliminary studies showing that: 1) inflammation coordinately stimulates p38 and -catenin phosphorylation in CRC cells; 2) p38 directly phosphorylates -catenin at S605, which increases -catenin stability, the -catenin-TCF4 interaction, Wnt transcription and CRC growth; 3) inflammation activates p38, but not p38, in intestinal tissues of mice, and IEC-specific p38 knockout (KO) reduces pro-inflammatory cytokine expression and attenuates colitis severity; 4) IEC p38 KO inhibits colon tumorigenesis and p--catenin/S605/Wnt signaling in the azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model of colitis-associated cancer (CAC); 5) the p38 pharmacological inhibitor pirfenidone (PFD) suppresses -catenin/cytokine expression and colon tumorigenesis in wild-type (WT) mice, but not in p38 KO mice, and further collaborates with the -catenin-TCF4 interaction antagonist LF3 and chemotherapeutic drug 5FU to inhibit CRC growth, and 6) p38 is upregulated in clinical CAC specimens and in intestinal tissues of Apcmin and interleukin-10 knockout (IL-10-/-) mice. These results together indicate that IEC p38 is required for tumorigenesis of both CAC and sporadic CRC by stimulating oncogenic -catenin phosphorylation. Using genetic and pharmacological approaches, we will test this hypothesis by determining (1) if p38- induced -catenin/S605 phosphorylation stimulates -catenin nuclear translocation, -catenin-TCF4 interaction, Wnt transcription and CRC growth; (2) if IEC-specific p38 KO blocks tumorigenesis in IL- 10-/- and Apcmin mice and if p38 is essential for the -catenin/TCF4/Wnt signaling to promote malignant progression in CRC pathogenesis; and (3) if the p38 pharmacological inhibitor pirfenidone (PFD) blocks CRC tumorigenesis and increases the growth-inhibitory activity of LF3 and 5FU by disrupting the p38/-catenin/TCF4/Wnt pathway. Upon completion, these studies will demonstrate if epithelial p38 promotes CRC tumorigenesis by stimulating oncogenic -catenin/S605 phosphorylation and Wnt transcription. Demonstrating the effectiveness of PFD in inhibiting Wnt signaling and CRC tumorigenesis by targeting intestinal epithelial p38 will reveal that drugging p38 has a great potential for colon cancer targeted therapy.

结直肠癌 (CRC) 是美国恶性相关死亡的第二大原因炎症是其发育、生长和进展的关键驱动力，p38 是 p38 的成员。丝裂原激活蛋白激酶（p38 MAPK   和 ）具有致癌性、促炎性和在临床 CRC 中过度表达，但上皮 p38 在 CRC 肿瘤发生中的作用尚未得到测试。连环蛋白是 Wnt 转录的关键辅助因子，在 90% 的 CRC 中被异常激活，而 β-连环蛋白却被异常激活。不可成药，因此迫切需要确定可成药的 β-连环蛋白激活剂用于治疗在此，我们提出肠上皮细胞 (IEC) 中的 p38 MAPK 驱动 CRC。通过刺激致癌的-连环蛋白磷酸化来促进肿瘤发生。这一假设基于我们的初步研究表明：1）炎症协调刺激 CRC 细胞中 p38- 和 β-catenin 磷酸化；2) p38- 在 S605 处直接磷酸化 β-catenin，这增加 -连环蛋白稳定性、-连环蛋白-TCF4 相互作用、Wnt 转录和 CRC 生长 3) 炎症激活小鼠肠道组织中的 p38，但不激活 p38，以及 IEC 特异性 p38 敲除 (KO) 4) IEC p38 KO 抑制结肠氧化偶氮甲烷 (AOM)/葡聚糖硫酸钠 (DSS) 中的肿瘤发生和 p--连环蛋白/S605/Wnt 信号传导结肠炎相关癌症 (CAC) 小鼠模型；5) p38 药理学抑制剂吡非尼酮 (PFD) 在野生型 (WT) 小鼠中抑制 -连环蛋白/细胞因子表达和结肠肿瘤发生，但在 p38 KO 中则不然小鼠，并进一步与-catenin-TCF4相互作用拮抗剂LF3和化疗药物合作 5FU 抑制 CRC 生长，并且 6) p38 在临床 CAC 标本和肠道组织中上调 Apcmin 和白细胞介素 10 敲除 (IL-10-/-) 小鼠这些结果共同表明 IEC p38 是必需的。通过刺激致癌的 β-连环蛋白磷酸化来抑制 CAC 和散发性 CRC 的肿瘤发生。使用遗传和药理学方法，我们将通过确定 (1) 如果 p38- 诱导的 -catenin/S605 磷酸化刺激 -catenin 核转位，-catenin-TCF4 相互作用、Wnt 转录和 CRC 生长；(2) IEC 特异性 p38 KO 是否能阻断 IL-中的肿瘤发生 10-/- 和 Apcmin 小鼠，如果 p38 对于 -catenin/TCF4/Wnt 信号传导促进恶性 CRC 发病机制；和进展 (3) 如果 p38 药物抑制剂吡非尼酮 (PFD) 通过破坏 LF3 和 5FU 来阻断 CRC 肿瘤发生并增加生长抑制活性 p38/-连环蛋白/TCF4/Wnt 通路完成后，这些研究将证明上皮 p38 是否存在。通过刺激致癌的 -catenin/S605 磷酸化和 Wnt 转录来促进 CRC 肿瘤发生。证明 PFD 通过靶向抑制 Wnt 信号传导和 CRC 肿瘤发生的有效性肠上皮p38将揭示药物p38在结肠癌靶向治疗方面具有巨大潜力。