Modulation of TRAIL signaling for cancer therapy.

Apoptosis, the cell's intrinsic death program, is a key regulator of tissue homeostasis, and an imbalance between cell death and proliferation may result in tumor formation. Also, killing of cancer cells by cytotoxic therapies such as chemotherapy, gamma-irradiation or ligation of death receptors is predominantly mediated by triggering apoptosis in target cells. Tumor necrosis factor-related apoptosis-inducing ligans (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis upon binding to its receptors. TRAIL is of special interest for cancer therapy, because TRAIL has been shown to predominantly kill cancer cells, while sparing normal cells. Importantly, combined treatment with TRAIL together with chemotherapy or gamma-irradiation synergized to achieve antitumor activity in tumor cell lines and also in tumor models in vivo. However, failure to undergo apoptosis in response to TRAIL treatment may result in tumor resistance. Understanding the molecular events that regulate TRAIL-induced apoptosis and their deregulation in resistant forms of cancer may provide new opportunities for cancer therapy. Thus, novel strategies targeting tumor cell resistance will be based on further insights into the molecular mechanisms of cell death, e.g., triggered by TRAIL.