TNF-related apoptosis-inducing ligand (TRAIL): A new path to anti-cancer therapies

Abstract

Since its discovery in 1995, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor super family, has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. Consequently, activation of the apoptotic signaling pathway from the death-inducing TRAIL receptors provides an attractive, biologically-targeted approach to cancer therapy. A great deal of research has focused on deciphering the TRAIL receptor signaling cascade and intracellular regulation of this pathway, as many human tumor cells possess mechanisms of resistance to TRAILinduced apoptosis. This review focuses on the currently state of knowledge regarding TRAIL signaling and resistance, the preclinical development of therapies targeted at TRAIL receptors and modulators of the pathway, and the results of clinical trials for cancer treatment that have emerged from this base of knowledge. TRAIL-based approaches to cancer therapy vary from systemic administration of recombinant, soluble TRAIL protein with or without the combination of traditional chemotherapy, radiation or novel anticancer agents to agonistic monoclonal antibodies directed against functional TRAIL receptors to TRAIL gene transfer therapy. A better understanding of TRAIL resistance mechanisms may allow for the development of more effective therapies that exploit this cell-mediated pathway to apoptosis.

How life changes itself: The Read–Write (RW) genome

“…But most cells execute the apoptosis decision based on the influence of signaling molecules in the environment [168]. Certain cell-cell signaling molecules serve as "death factors" and promote apoptosis (e.g., tumor necrosis factor, TNF [169]), while other signals generally described as "growth factors" bias the decision towards cell cycle arrest and repair [170].…”

Epigenetic inactivation of T-box transcription factor 5, a novel tumor suppressor gene, is associated with colon cancer

“…These effectors further initiate the proteolytic cleavage of the nuclear enzyme poly-(ADP-ribose) polymerase, which caused loss of DNA repair, cellular disassembly and finally undergo apoptosis ( Figure 5). Apoptosis induced by extrinsic pathways has been considered to be an important antitumor mechanism (Johnstone et al, 2008;Balkwill, 2009;Holoch and Griffith, 2009). Another important pro-apoptotic activator induced by TBX5 is BAX.…”

The trail to deadly membrane rafts

“…Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) may stimulate death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2) antagonizing DR4 and DR5, and osteoprotegerin, a regulator of osteoclastogenesis and soluble TRAIL receptor [1]. All five receptors are expressed in endothelial cells and participate in the regulation of inflammation, proliferation, differentiation, and apoptosis [1].…”

“…All five receptors are expressed in endothelial cells and participate in the regulation of inflammation, proliferation, differentiation, and apoptosis [1]. Accordingly, TRAIL may stimulate or inhibit apoptosis.…”