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

肿瘤细胞在化疗中存活的能力是治愈癌症患者的主要障碍。癌细胞产生多药耐药(MDR)的一个机制是它们获得了一种称为P-糖蛋白(P-gp)的细胞表面蛋白的表达，这种蛋白通过泵机制将细胞毒药排出癌细胞。最近，我们证明了P-gp除了起到清除细胞内药物的作用外，还能保护细胞免受药物以外的刺激所致的死亡，而药物的外排作用则没有明显的益处。P-gp增强细胞存活的更广泛的作用可能是因为它能够调节细胞内存在的关键酶的活性，在适当的时候诱导细胞自杀。一些化疗药物激活这些死亡酶(Caspase)来杀死靶细胞，因此P-gp可能通过将药物从靶细胞中移除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，我们还确定了P-gp在正常细胞中保持低表达，而在许多多药耐药肿瘤细胞中上调的方式。似乎表达P-gp的基因(称为mdr1)被包装在染色体内的方式调节着基因的表达水平。我们现在正在鉴定参与调节MDR1表达的蛋白质和复合体，以充分确定在P-gp表达的MDR肿瘤表现过程中发生的分子事件。我们的新发现可能为MDR癌症患者带来新的治疗选择，并可能为最初抑制P-gp表达MDR肿瘤的可能新方法提供洞察力。

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.