TNF Family Receptors: On the TRAIL of Novel Cancer Therapeutics

One of the many functions that the cytokine tumor necrosis factor (TNF) performs is to induce apoptosis, or programmed cell death. Cells die off regularly to be replaced with new ones in the normal course of tissue development, maintenance and repair, and humans turn over roughly 1.4 kilograms of cells per day. Intervening with cell signaling to stimulate apoptosis has been a target for cancer treatment¹ because cancer cells proliferate uncontrollably, leading to tumors and other cancerous abnormalities.

When bound to TNF receptors found on the outside of cell membranes, TNF triggers an enzyme cascade that leads to a cell’s death. To stimulate apoptosis, therapeutics can increase the amount of circulating TNF and improve specificity by increasing tumor necrosis factor-related ligands (TRAIL).²

Although there are TRAIL ligands (Fas) which trigger a stronger response, drug discovery researchers are working to identify any method through which to induce apoptosis in cancer cells. Other tumor necrosis factor-related ligands (TRAIL) of interest are TRAIL-1 and TRAIL-2. TRAIL is an attractive candidate because it induces apoptosis in a range of tumor cells, but not in normal cells as does TRAIL-Fas.³

Proteomics researchers have shown that when TRAIL-1 or TRAIL-2 or both bind to cancer cell receptors, pro-caspase 8 activates caspase-8 to release a chain of caspases leading to cell death.³ One recent study has determined that TRAIL-2 showed greater response than TRAIL-1, suggesting that therapies targeting TRAIL-2 up-regulation may be more successful than those targeting TRAIL-1.¹

In vitro studies have also shown that the upregulation of TRAIL-1 and TRAIL-2 improves cell death rates in several cancer cells.^2,4 However, certain cancer types (glioma, colorectal) can develop TRAIL resistance. To combat resistance, researchers have combined traditional chemotherapeutics with TRAIL-based compounds. In recent years, many drugs have been screened for their ability to restore TRAIL sensitivity. For example, in a recent study of brain cancer glia, cancerous cells pretreated with paclitaxel and then treated with TRAIL agents showed significantly reduced resistance as well as higher overall apoptosis rates.⁴

A review of numerous chemotherapeutic compounds for treating TRAIL resistance in colorectal cancer lists many effective agents, though suggests we should continue to investigate other natural and synthetic agents that might produce fewer toxic side effects.² The promise of TRAIL-based therapies remains attractive and may still prove more effective than existing chemotherapies alone. However, the initial attraction was to develop a TRAIL-based therapy targeted only to malignant cells. If TRAIL drugs must be accompanied by traditional toxic therapeutics, their clinical usefulness may eventually be eclipsed by other strategies.

References

1 Szegezdi, E., et al. (2012) ‘Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: Apoptosis induction by TRAIL‘, Molecular and Cellular Proteomics, 11 (3), (p. M111.013730)

2 Stolfi, C., et al. (2012) ‘Molecular targets of TRAIL-sensitizing agents in colorectal cancer‘, International Journal of Molecular Sciences, 13 (7), (pp. 7886-7901)

3 Neumann, S., et al. (2012) ‘The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity‘, PLoS One, 7 (8), (p. e42526)

4 Qiu, B., et al. (2012) ‘TRAIL and paclitaxel synergize to kill U87 cells and U87-derived stem-like cells in vitro‘, International Journal of Molecular Sciences, 13 (7), (pp. 9142-9156)