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 protein called P-glycoprotein (P-gp) that extrudes cytotoxic drugs out of the cancer cell. We have defined a novel role for P-gp in protecting cells against death induced by non-drug stimuli, where an efflux effect of P-gp would have no obvious benefit. This broader survival effect of P-gp may be explained by its ability to regulate the activity of key enzymes (caspases) that exist within cells to induce cell suicide when appropriate. Many chemotherapeutic drugs activate caspases to kill target cells and as P-gp can inhibit caspase activation, 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 a cell. We have mutated P-gp to define the region that is necessary for its caspase regulatory function. We are now identifying the proteins that bind to this region so that we can determine how P-gp regulates caspase activation. In addition, we have defined the manner by which P-gp expression is kept low in normal cells and is upregulated following exposure of cells to chemotherapeutic drugs. The gene encoding P-gp (MDR1) is normally switched off due to the way it is packaged within a nuclear structure called chromatin. We have shown that treatment of cancer cell lines with chemotherapeutic drugs alters chromatin in such a way that the MDR1 gene is activated. We will identify the proteins and complexes involved in drug-mediated regulation of chromatin structure and determine if this phenomenon occurs within patients receiving chemotherapy. 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.