Function of Verticillin A in Suppression of MDSC and CRC Stem Cells

项目摘要 目前，转移性结直肠癌（CRC）患者的5年生存率仅为8%左右。 绝大多数CRC死亡率是由于癌细胞对现有治疗剂的耐药性。因此，我们认为， 迫切需要开发能够抑制耐药性转移性CRC的新药物。我们有 从野生蘑菇中提纯的一种化合物，具有很强的抗肿瘤活性。该化合物被鉴定为 维替西林A我们证明轮枝青霉素A修饰BNIP 3启动子染色质组蛋白结构， 克服DNA甲基化的沉默效应以激活转移性人CRC中的BNIP 3转录 细胞有趣的是，我们的初步研究表明，Verticillin A有效抑制药物- 抵抗CRC干细胞生长。我们的长期目标是开发Verticillin A作为治疗药物， 治疗患有转移性CRC的人类患者。本项目的目标是阐明 Verticillin A作用的潜在分子机制，并确定Verticillin A是否可以 在体内有效抑制MDSC和耐药CRC干细胞。我们建议采取以下措施 三个目的：1）确定BNIP 3启动子染色质中DNA和H3 K9甲基化的网络， 在人CRC细胞中介导BNIP转录抑制; 2）检验轮状青霉素A 靶向组蛋白甲基化以激活BNIP 3转录并抑制5-FU的自发转移。 3）检验轮替西林A和5-FU协同诱导耐药CRC干细胞的假设 MDSC凋亡和抑制MDSC积聚。成功完成这些拟议的研究， 开发Verticllin A作为治疗5-FU耐药人类患者的有效药物的潜力 窝藏egdr突变

Project Summary The current 5-year survival rate for patients with metastatic colorectal cancer (CRC) is only about 8%. The vast majority of CRC mortality is due to cancer cell resistance to existing therapeutic agents. Therefore, development of novel agents that can suppress drug-resistant metastatic CRC is in urgent need. We have purified from wild mushroom a compound with potent anti-tumor activity. This compound was identified as Verticillin A. We demonstrated that Verticillin A modifies the BNIP3 promoter chromatin histone structure to over-ride the silencing effect of DNA methylation to activate BNIP3 transcription in metastatic human CRC cells. Interestingly, our preliminary studies revealed that Verticillin A is effective in suppression of drug- resistant CRC stem cell growth. Our long-term objective is to develop Verticillin A as a therapeutic agent for treatment of human patients with metastatic CRC. The objectives of this project are to elucidate the underlying molecular mechanisms of Verticillin A action and to determine whether Verticillin A can effectively suppress MDSC and drug-resistant CRC stem cells in vivo. We propose to pursue the following three aims: 1) determine the network of DNA and H3K9 methylation in the BNIP3 promoter chromatin that mediates BNIP transcriptional repression in human CRC cells; 2) test the hypothesis that Verticillin A targets histone methylation to activate BNIP3 transcription and suppress spontaneous metastasis of 5-FU- resistant CRC stem cells in vivo; and 3) test the hypothesis that Verticillin A and 5-FU cooperate to induce MDSC apoptosis and suppress MDSC accumulation. Successful completion of these proposed studies has the potential to develop Verticllin A as an effective drug for treatment of human patients with 5-FU-resistant metastatic colorectal cancer.