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

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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.