Conclusion: HCV genotype 3a has the tendency to induce both intrinsic and extrinsic pathways
of apoptosis in peripheral blood mononuclear cells, facilitating HCV infection of hepatocytes by inhibiting the cells related to immune system.
Inhibition of the extrinsic pathway
by CASP8 and CASP10 inhibitors reduced apoptosis significantly.
Key Role of the Extrinsic Pathway
of Blood Coagulation in Hemostasis and Thrombosis.
(1) The extrinsic pathway
mediated by death receptors, (2) the intrinsic pathway centered on mitochondria, and (3) the perforin pathway induced by granzyme B.
In the extrinsic pathway
, apoptosis is mediated by death receptors.
There are two major pathways in mammalian cells leading to classical apoptosis: the caspase-8-initiated intrinsic and the caspase-9-dependent extrinsic pathways
Thus, MJ induced the expression of TNFR1 in human breast MCF-7 and MDA-MB-435 cells [25, 74] and in hormone-independent human prostate PC-3 and DU 145 cancer cells promoting apoptosis by the extrinsic pathway
in these cells .
The extrinsic pathway
is triggered when death ligands bind to their respective cell surface death receptors through recruitment of FAS-associated death domain (FADD) protein, procaspase-8 through the formation of a complex that induces cell death and activation of the caspases (caspase-8 and caspase-10).
In the extrinsic pathway
, nuclear p53 increases the expression of death receptors such as the APO-1/Fas receptor  and the TRAIL receptor (DR4/5) ; while cytoplasmic p53 activates caspase 8 and caspase 3.
Apoptosis occurs through two main pathways: the extrinsic pathway
triggered by ligands binding to cell death receptors, the intrinsic or mitochondrial pathway initiated by genotoxic stress.
The results of these studies also suggest the inhibition of NF-kB activation, the suppression of anti-apoptotic proteins, such as IAP, c-FLIP, Akt kinase, and the initiation of extrinsic pathway
of apoptosis by induction of TRAIL and Fas receptor stimulation in cancer cells.
The activation of cell surface death receptors by tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and death receptor agonists represent an attractive therapeutic strategy to promote apoptosis of tumor cells through the activation of the extrinsic pathway
. The observation that Apo2L/TRAIL can eliminate tumor cells preferentially over normal cells has resulted in several potential therapeutics that exploit the extrinsic pathway
, in particular, the soluble recombinant human (rh)Apo2L/TRAIL protein and agonist monoclonal antibodies that target death receptors 4 or 5.