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.
Fulda
Simone
S
University Children's Hospital, D-89075 Ulm, Germany.
Debatin
Klaus-Michael
KM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000009:adverse effects / Q000502:physiology* / Q000627:therapeutic use; D016328:NF-kappa B; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000502:physiology* / Q000627:therapeutic use
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha