Characterisation of the anti-apoptotic function of P-glycoprotein and transcriptional regulation of the MDR1 gene

P-糖蛋白抗凋亡功能的表征和 MDR1 基因的转录调控

• 批准号: nhmrc : 208930
• 负责人: Prof Assam El-Osta
• 金额: $ 21.61万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2002
• 资助国家: 澳大利亚
• 起止时间: 2002-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/characterisation-anti-apoptotic-mdr1-gene/94731
• 关键词: Characterisation; anti; apoptotic; function; glycoprotein

The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a cell surface protein called P-glycoprotein (P-gp) that serves to extrude cytotoxic drugs out of the cancer cell via a pumping mechanism. Recently, we demonstrated, that in addition to its role in removing drugs from cells, P-gp can also protect cells against death induced by stimuli other than drugs where an efflux effect of P-gp would have no obvious benefit. This broader effect of P-gp to enhance cell survival may be explained by its ability to regulate the activity of key enzymes that exist within cells to induce cell suicide when appropriate. Some chemotherapeutic drugs activate these death enzymes (caspases) to kill target cells and it is therefore possible that P-gp affects the activity of anti-cancer drugs by both removing the drugs from the target cells and inhibiting the pathways through which the drugs can kill the cell. We are now determining how P-gp affects the activity of caspases. In addition, we have defined the manner by which P-gp expression is kept low in normal cells and is upregulated in many MDR tumor cells. It appears that the way the gene expressing P-gp (called MDR1) is packaged within chromosomes regulates gene expression levels. We are now identifying the proteins and complexes involved in regulating MDR1 expression to fully determine the molecular events that occur during the manifestation of a P-gp-expressing MDR tumor. Our new findings may lead to novel treatment options for patients that have MDR cancers and may provide insight into possible new ways to inhibit the formation of P-gp-expressing MDR tumors in the first place.

肿瘤细胞在化疗治疗中存活的能力是治愈癌症患者的主要障碍。癌细胞成为多药耐药（MDR）的一种机制是它们获得性表达称为P-糖蛋白（P-gp）的细胞表面蛋白，其用于通过泵送机制将细胞毒性药物挤出癌细胞。最近，我们证明，除了其在从细胞中去除药物的作用，P-gp也可以保护细胞免受由药物以外的刺激诱导的死亡，其中P-gp的外排效应将没有明显的益处。P-gp增强细胞存活的这种更广泛的作用可以通过其调节细胞内存在的关键酶的活性以在适当时诱导细胞自杀的能力来解释。一些化疗药物激活这些死亡酶（半胱天冬酶）以杀死靶细胞，因此P-gp可能通过从靶细胞中去除药物并抑制药物杀死细胞的途径来影响抗癌药物的活性。我们现在正在确定P-gp如何影响caspase的活性。此外，我们已经确定了P-gp表达在正常细胞中保持低水平，而在许多MDR肿瘤细胞中上调的方式。似乎表达P-gp（称为MDR 1）的基因在染色体内的包装方式调节基因表达水平。我们现在正在鉴定参与调节MDR 1表达的蛋白质和复合物，以充分确定在表达P-gp的MDR肿瘤表现期间发生的分子事件。我们的新发现可能会为MDR癌症患者带来新的治疗选择，并可能为抑制表达P-gp的MDR肿瘤形成提供新的可能方法。