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[TNF-related apoptosis-inducing ligand signaling pathway and hematopoietic malignancies]
1Leukemia Research Unit, The First Affiliated Hospital, Suzhou University, Suzhou 215006, China.
Abstract:
TNF-related apoptosis-inducing ligand (TRAIL) is a newly identified member of the tumor necrosis factor (TNF) family. TRAIL induces apoptosis by activating caspase cascades, stimulating a loss of mitochondrial membrane potential (Delta Psim) and cytochrome C release in the FADD/caspase-8 dependent pathway. However, TRAIL can also trigger transcriptional activations of the pro-oncogene of c-fos, JNK, and NF-kappaB by other signaling pathways downstream of FADD/caspase-8. MAPK/ERK activation has a dominant protecting effect over apoptotic signaling from the death receptors. The functional expression of TRAIL by leukemic cells may be involved in tumor cells evasion of immunosurveillance. Somatic mutations of TRAIL-R1 and TRAIL-R2 genes may play a role in the pathogenesis of some tumors. TRAIL can induce apoptosis on various continuous transformed cell lines and primary tumor cells, including several of hematopoietic origin, displaying minimal toxic effects on normal tissues. Because of the abilities of induction of both cytotoxic (apoptosis) and cytostatic (cell cycle perturbation) effects on the leukemic cells, TRAIL is currently considered as a potential(co) therapeutic drug against tumors.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells while sparing normal tissues. Its dual cytotoxic and cytostatic effects make TRAIL a promising therapeutic agent for tumors.
Area of Science:
- Molecular Biology
- Immunology
- Oncology
Context:
- TNF-related apoptosis-inducing ligand (TRAIL) is a key mediator of apoptosis.
- TRAIL activates caspase cascades, leading to programmed cell death.
- TRAIL signaling involves FADD/caspase-8 dependent pathways and downstream effectors.
Purpose:
- To investigate the mechanisms of TRAIL-induced apoptosis and its potential therapeutic applications.
- To explore TRAIL's role in cancer immune evasion and pathogenesis.
- To evaluate TRAIL's efficacy against various cancer cell lines, including hematological malignancies.
Summary:
- TRAIL induces apoptosis via caspase activation, mitochondrial disruption, and cytochrome C release.
- TRAIL can also activate pro-oncogenic pathways like c-fos, JNK, and NF-kappaB.
- MAPK/ERK signaling can counteract TRAIL-mediated apoptosis.
- Functional TRAIL expression by leukemic cells may facilitate immune evasion.
- Somatic mutations in TRAIL-R1/R2 genes could contribute to tumor development.
- TRAIL effectively induces apoptosis and cell cycle arrest in diverse tumor cells with minimal toxicity to normal tissues.
Impact:
- TRAIL demonstrates significant cytotoxic and cytostatic effects on leukemic cells.
- TRAIL is recognized as a potential co-therapeutic agent for cancer treatment.
- Understanding TRAIL's complex signaling pathways is crucial for optimizing its clinical use.