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Multidrug resistance mediated by the drug-efflux protein P-glycoprotein (P-gp) is one mechanism that tumor cells use to escape death induced by chemotherapeutic drugs. Although it is irrefutable that P-gp can efflux xenobiotics out of cells, biological regulatory functions for P-gp in multicellular organisms have yet to be established firmly. Recent observations have challenged the notion that P-gp has evolved merely to efflux xenotoxins out of healthy cells and raised the possibility that P-gp and related transporter molecules might play a fundamental role in regulating cell differentiation, proliferation and survival.

Human GraB (hGraB) preferentially induces apoptosis via Bcl-2-regulated mitochondrial damage but can also directly cleave caspases and caspase substrates in cell-free systems. How hGraB kills cells when it is delivered by cytotoxic lymphocytes (CL) and the contribution of hGraB to CL-induced death is still not clear. We show that primary human natural killer (hNK) cells, which specifically used hGraB to induce target cell death, were able to induce apoptosis of cells whose mitochondria were protected by Bcl-2. Purified hGraB also induced apoptosis of Bcl-2-overexpressing targets but only when delivered at 5- to 10-fold the concentration required to kill cells expressing endogenous Bcl-2. Caspases were critical in this process as inhibition of caspase activity permitted clonogenic survival of Bcl-2-overexpressing cells treated with hGraB or hNK cells but did not protect cells that only expressed endogenous Bcl-2. Our data therefore show that hGraB triggers caspase activation via mitochondria-dependent and mitochondria-independent mechanisms that are activated in a hierarchical manner, and that the combined effects of Bcl-2 and direct caspase inhibition can block cell death induced by hGraB and primary hNK cells.Cell Death and Differentiation (2008) 15, 708–717; doi:10.1038/sj.cdd.4402300; published online 18 January 2008 [ABSTRACT FROM AUTHOR]

Previous studies by our laboratory have shown that the drug transporter protein P-glycoprotein, P-gp, can specifically inhibit Fas-induced caspase-3 activation and apoptosis. Importantly, inhibition of both caspase-3 activation and cell death could be reversed by pharmacological and antibody inhibitors of P-gp function. However, the molecular mechanisms underpinning P-gp-mediated resistance to Fas-induced cell death and caspase activation remained unknown. We therefore sought to identify the point(s) within the death receptor pathway at which P-gp exerted its inhibitory effect and to determine whether the ATPase activity of P-gp was required. Structure-function analysis determined that ATP hydrolysis was necessary for P-gp to confer resistance to Fas-induced caspase activation and cell death. Importantly, although both FADD and caspase-8 were recruited to the Death Inducing Signal Complex (DISC) in wild-type P-gp expressing cells following Fas ligation, subsequent activation of caspase-8 at the DISC was inhibited. The ability of P-gp to inhibit caspase-8 activation was also ATP dependent. These studies demonstrate that P-gp inhibits Fas-induced caspase-8 activation but not formation of the DISC and that this activity of P-gp is dependent on ATP hydrolysis.Cell Death and Differentiation (2002) 9, 1266–1272. doi:10.1038/sj.cdd.4401081 [ABSTRACT FROM AUTHOR]

The article offers information on the First Australian Workshop, on Cell Death, conducted from August 21-25, 2011, in Lindermann Island, Australia. Topics included ligation of death receptors, proteins altering sensitivity of cells, and cell death. A new role for heat shock protein 70 was shown through a model, in tumor cell clearance by promoting anti-tumor immunity.