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Unveiling Fas signaling: How does it impact cancer therapy?
In the regulation of the immune system, the role of Fas ligand (FasL or CD95L) cannot be ignored. As a class II transmembrane protein expressed in a variety of cell types, FasL can bind to its receptor Fas, thereby promoting the process of apoptosis. The impact of this complex signaling mechanism on cancer treatment makes people think deeply about its potential application value.
Structural Characteristics
FasL belongs to the tumor necrosis factor superfamily (TNFSF). Its structure is a trimer, consisting of three identical polypeptides. FasL possesses a long cytoplasmic domain, a rod region and a transmembrane region, and possesses a TNF homology domain that plays an important role in homotrimerization. This structural feature enables it to effectively bind to the Fas receptor and initiate the signaling pathway.
Receptor interaction
The Fas receptor (FasR or CD95) is the best-studied member of the death receptor family. FasR is located on human chromosome 10, and up to eight splice variants have been discovered that translate into seven different protein homologues. The functions of these homologs are closely related to disease states.
DcR3 (Decoy receptor 3) is a newly discovered decoy receptor of the tumor necrosis factor superfamily. It can bind FasL and its analogs and has no signal transduction ability.
Cell signaling and mechanisms
The Fas signaling pathway is initiated mainly through the interaction between Fas receptors and Fas ligands. When membrane-anchored FasL binds to FasR on neighboring cells, a death-inducing signaling complex (DISC) is formed. Next, the FADD protein binds to the Fas receptor through its death domain and promotes apoptotic enzyme activation.
Activated caspase-8 will be released into the cytoplasm, thereby promoting further apoptotic processes, such as DNA degradation and cell membrane changes. It is worth noting that some cells show high sensitivity to Fas-induced apoptosis, known as type 1 cells, and anti-apoptotic Bcl-2 family members are almost unable to prevent their apoptotic process.
The function of apoptosis in the immune system
Apoptosis triggered by the binding of Fas receptor-Fas ligand plays a crucial role in regulating the immune system. This includes:
T cell constancy: T cells are initially resistant to Fas-mediated apoptosis, but as the activation time prolongs, their sensitivity gradually increases, eventually leading to activation-triggered cell death (AICD).Activity of cytotoxic T cells: Fas-induced apoptosis and the perforin pathway are the main mechanisms of cytotoxic T cell-induced death.Uterine tolerance: Fas ligand may play an important role in preventing the transfer of white blood cells between mother and fetus.
Unfortunately, tumors may overexpress Fas ligand, inducing apoptosis in infiltrating lymphocytes and thereby evading the effects of the immune response.
Role in disease
Defects in Fas-mediated apoptosis may lead to cancer development and drug resistance of existing tumors. For example, genetic mutations in Fas are associated with autoimmune lymphoproliferative syndrome (ALPS), while enhanced Fas signaling is associated with low-risk myelodysplastic syndromes (MDS) and glioma pathology.
In addition, FasL-mediated T cell apoptosis is also considered to be a mechanism for tumors to evade immune check, similar to inhibitory immune checkpoints such as PD-1 and CTLA-4.
Future Outlook
As research on Fas signaling gradually deepens, scientists begin to explore the application of this pathway in cancer treatment. Targeting therapy using Fas signaling may provide new ideas and strategies for the development of tumor immunotherapy. However, we still need to deeply understand the role of this pathway in different tumor types and its regulatory mechanisms.
In such a changing research field, what kind of changes can the fine regulation of Fas signaling bring to future cancer treatment?
