Targeting TGFbeta/PDK4 to Overcome Drug Resistance in Colorectal Cancer

靶向 TGFbeta/PDK4 克服结直肠癌耐药性

• 批准号: 9383780
• 负责人: Jing Wang
• 金额: $ 34.64万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-22 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383780
• 关键词: Apoptosis; Biological; Cancer Etiology; Cells; Cessation of life; Clinical Trials; Colon Carcinoma; Colorectal Cancer; DNA; Development; Drug resistance; Effectiveness; Event; Feedback; Fluorouracil; Glycolysis; Human; Knowledge; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Molecular; Neoplasm Metastasis; PDH kinase; Pathway interactions; Patients; Play; Primary Neoplasm; Process; Protein Isoforms; RNA; Resistance; Role; Sampling; Signal Transduction; Specimen; Testing; Time; Transforming Growth Factor beta; Treatment Failure; Treatment outcome; Tumor Burden; United States; Up-Regulation; base; cancer cell; cancer therapy; chemotherapy; clinically relevant; clinically significant; colon cancer patients; cytotoxicity; design; differential expression; effective therapy; experimental study; glucose metabolism; improved; in vivo; inhibitor/antagonist; knock-down; metastatic colorectal; mortality; mouse model; mutant; novel; oxaliplatin; prognostic value; pyruvate dehydrogenase; resistance mechanism; response; tumor growth; tumor xenograft

Abstract Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA. The failure of treatment is due to resistance to chemotherapy, one of the biggest obstacles for effective cancer therapy. Therefore, there is an urgent need to identify molecules or pathways that can be targeted to overcome drug resistance and improve cancer treatment. TGFβ plays multiple functions including conferring drug resistance. However, the mechanisms underlying TGFβ-mediated chemoresistance are not clear. PDK4 is one of the isoforms of pyruvate dehydrogenase kinase (PDK), which phosphorylate pyruvate dehydrogenase (PDH) and regulate glucose metabolism. We have discovered a novel function of PDK4 that mediates the response of colon cancer cells to 5-FU treatment. We show that PDK4, but not PDK 1-3, is differentially expressed in colon cancer cells, and that its expression positively correlates with the resistance to 5-FU treatment. Knockdown of PDK4 sensitizes colon cancer cells to 5-FU- or oxaliplatin-induced apoptosis. Experiments in tumor xenograft mouse models demonstrate that knockdown of PDK4 increases the effectiveness of 5-FU-mediated inhibition of tumor growth in vivo. Furthermore, for the first time, we have established a novel crosstalk between TGFβ signaling and PDK4: TGFβ increases PDK4 expression while PDK4 enhances TGFβ signaling, which forms a positive feedback loop. Elevated PDK4 expression contributes to TGFβ-mediated drug resistance in colon cancer cells. Studies of patient samples indicate that expression of PDK4 and TGFβ signaling positively correlate with each other and with chemoresistance in CRC. Therefore, our studies unveil an important function of TGFβ/PDK4 in mediating drug resistance in CRC. In this proposal, we will determine the mechanism(s) underlying the crosstalk between TGFβ signaling and PDK4, elucidate the mechanism(s) of PDK4-mediated drug resistance and identify novel substrates of PDK4. We will determine the functional role of PDK4 in colon cancer metastasis and the contribution of PDK4 and its crosstalk with TGFβ in CRC drug resistance using an orthotopic mouse model. We will also demonstrate the clinical relevance in patient samples. The completion of these studies will identify TGFβ/PDK4 as a novel regulator of chemoresistance in CRC, substantially advance our understanding of molecular mechanisms underlying drug resistance and provide proof-of-concept that combinations of 5-FU with inhibitors of PDK4 or TGFβ could be potentially effective therapies to overcome chemoresistance for CRC treatment.

抽象的 结直肠癌（CRC）是美国癌症死亡率的第二大原因。 治疗失败是由于对化学疗法的抵抗，这是最大的障碍之一 有效的癌症治疗。因此，迫切需要识别分子或途径 可以针对克服耐药性和改善癌症治疗的目标。 TGFβ扮演着多种功能，包括会议耐药性。但是， TGFβ介导的化学抗性的基础机制尚不清楚。 PDK4是 丙酮酸脱氢酶激酶（PDK）的同工型，丙酮酸丙酮酸磷酸盐 脱氢酶（PDH）并调节葡萄糖代谢。我们发现了一个新功能 PDK4介导结肠癌细胞对5-FU治疗的反应。我们表明 PDK4，但不是PDK 1-3在结肠癌细胞中的表达不同，并且其表达 与对5-FU治疗的耐药性正相关。敲低PDK4感应结肠 癌细胞至5-FU-或奥沙利铂诱导的细胞凋亡。肿瘤特征小鼠的实验 模型表明，PDK4的敲低增加了5-FU介导的有效性 抑制体内肿瘤生长。此外，我们第一次建立了一本小说 TGFβ信号传导与PDK4之间的串扰：TGFβ增加了PDK4的表达，而PDK4 增强TGFβ信号传导，形成正反馈循环。 PDK4表达升高 在结肠癌细胞中有助于TGFβ介导的耐药性。患者样品的研究 表明PDK4和TGFβ信号传导的表达彼此正相关，并且 CRC中的化学抗性。因此，我们的研究公开了 CRC中介导耐药性的TGFβ/PDK4。 在此提案中，我们将确定串扰之间的机制 TGFβ信号传导和PDK4，阐明了PDK4介导的耐药性和 识别PDK4的新型底物。我们将确定PDK4在结肠癌中的功能作用 转移和PDK4及其与TGFβ在CRC耐药性中的贡献 使用原位鼠标模型。我们还将证明患者的临床相关性 样品。这些研究的完成将确定TGFβ/PDK4作为新的调节剂 CRC中的化学抗性，大大提高了我们对分子机制的理解 潜在的耐药性，并提供5-FU组合的概念证明 PDK4或TGFβ的抑制剂可能是克服的潜在有效疗法 CRC治疗的化学抗性。