A Role for P-Glycoprotein in Regulating Cell Death

Abstract

P-glycoprotein (P-gp) is an energy dependent drug pump responsible for multidrug resistance (MDR) in human cancers. While it is irrefutable that P-gp can efflux xenobiotics out of cells, the biological function of P-gp in multicellular organisms has yet to be firmly established. The question of what, if anything, P-gp does when not effluxing drugs has been raised by recent reports indicating that P-gp may regulate apoptosis, chloride channel activity, cholesterol metabolism and immune cell function. There is now a lively debate regarding the possible role of P-gp in regulating cell differentiation, proliferation and survival.P-gp has been shown by many different investigators to function as an energy dependent drug pump and the fact that the molecule is highly conserved throughout evolution points to an indispensable function. However, the recent observations that P-gp may have other cellular functions is also compelling. The unexpected findings that P-gp is expressed on CD34+ stem cells, dendritic cells, NK cells and cytotoxic T lymphocytes raises the possibility that P-gp may play a role in hemopoietic development and immune cell function. It is conceivable that important progenitor cells would have mechanisms in place to protect them against apoptotic stimuli and it is tempting to speculate that P-gp could help serve this purpose. It is therefore possible that P-gp may serve to protect immune cells against stress-induced or bystander lysis in the hostile environment of sites of inflammation.