Targeting TGFbeta/PDK4 to Overcome Drug Resistance in Colorectal Cancer

靶向 TGFbeta/PDK4 克服结直肠癌耐药性

基本信息

批准号：
10000912
负责人：
Jing Wang
金额：
$ 35.69万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-16 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000912
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 drug resistance cancer therapy chemotherapy clinically relevant clinically significant colon cancer metastasis colon cancer patients colorectal cancer treatment 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 patient response prognostic value pyruvate dehydrogenase response tumor growth tumor xenograft

项目摘要

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）是美国癌症死亡的第二大原因。治疗失败是由于化疗耐药，这是治疗的最大障碍之一因此，迫切需要确定有效的癌症治疗分子或途径。可以有针对性地克服耐药性并改善癌症治疗。 TGFβ 具有多种功能，包括赋予耐药性。 PDK4 是其中之一，其机制尚不明确。丙酮酸脱氢酶激酶 (PDK) 的亚型，可磷酸化丙酮酸我们发现了脱氢酶（PDH）和调节葡萄糖代谢的新功能。 PDK4 介导结肠癌细胞对 5-FU 治疗的反应。 PDK4（而非 PDK 1-3）在结肠癌细胞中存在差异表达，并且其表达 PDK4 的敲除使结肠敏感，与 5-FU 治疗的耐药性呈正相关。肿瘤异种移植小鼠中 5-FU 或奥沙利铂诱导的癌细胞凋亡实验。模型表明 PDK4 的敲低可提高 5-FU 介导的有效性此外，我们首次建立了一种新的体内肿瘤生长抑制方法。 TGFβ 信号传导与 PDK4 之间的串扰：TGFβ 增加 PDK4 表达，而 PDK4 增强 TGFβ 信号传导，从而形成正反馈环路 PDK4 表达升高。有助于对患者样本进行 TGFβ 介导的耐药性研究。表明 PDK4 和 TGFβ 信号传导的表达彼此呈正相关，并且因此，我们的研究揭示了 CRC 的重要功能。 TGFβ/PDK4 介导 CRC 耐药性。在本提案中，我们将确定之间串扰的机制 TGFβ 信号传导和 PDK4，阐明 PDK4 介导的耐药机制鉴定 PDK4 的新底物我们将确定 PDK4 在结肠癌中的功能作用。转移以及 PDK4 及其与 TGFβ 串扰在 CRC 耐药中的作用我们还将使用原位小鼠模型来证明其临床相关性。这些研究的完成将确定 TGFβ/PDK4 是一种新型的调节因子。结直肠癌的化学耐药性，大大增进了我们对分子机制的理解潜在的耐药性并提供了 5-FU 与 PDK4 或 TGFβ 抑制剂可能是克服这一问题的潜在有效疗法 CRC 治疗的化疗耐药性。