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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：
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
项目类别：
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

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.

摘要