Promotion of Fas‐mediated apoptosis in Type II cells by high doses of hepatocyte growth factor bypasses the mitochondrial requirement

Abstract

The death receptor pathway is coupled to the mitochondria apoptosis pathway. However, mitochondrial participation, which is stimulated by Bid but suppressed by Bcl-2/Bcl-x L , is required in certain cells (Type II), but not in others (Type I). While these differences were originally characterized in the lymphoid cell lines, the typical Type II cells are represented by hepatocytes in vivo. The molecular mechanisms that distinguish Type II from Type I cells and the regulation are not fully understood. Fas can be sequestered by the HGF receptor c-Met and high doses of HGF can promote cell death by freeing Fas from c-Met complex. We thus reasoned that treatment of the Type II cells with high doses of HGF could enhance Fas-mediated apoptosis and spare the mitochondria amplification. Indeed, such treatment led to increased apoptosis in Type II lymphoid cells, which could not be blocked by Bcl-x L . Moreover, significant hepatocyte apoptosis was induced by this scheme in the absence of Bid with increased dissociation of Fas from c-Met. These findings indicate that high doses of HGF could be used to promote apoptosis in Type II cells bypassing the requirement for mitochondria activation.

Switch from type II to I Fas/CD95 death signaling on in vitro culturing of primary hepatocytes

“…In response to high levels of HGF or FasL, c‐Met is released from Fas, allowing FADD and caspase‐8 recruitment and apoptosis induction 35, 36. Interestingly, a recent report showed that high doses of HGF could bypass the mitochondrial requirement for Fas‐induced apoptosis in Jurkat cells and hepatocytes, leading to a type I signaling phenotype 37. Similarly, integrins could modulate the Fas, but not the TNF‐R1 DISC to engage type I instead of type II signaling.…”

Paradoxical action of growth factors: antiproliferative and proapoptotic signaling by HGF/c-MET

“…c-MET with FAS complex was also found in hepatoblastoma cells and breast neoplastic cells (Wang et al 2002), in normal B lymphocytes and in pediatric B acute lymphoblastic leukemia cells (REH) (Accordi et al 2007) as well as in some types of lymphoid cells (Zhao et al 2007).…”

Immunomodulatory Properties of Mesenchymal Stem Cells: Cytokines and Factors

“…103 Many papers have reported that c-Met and HGF are expressed together. [115][116][117][118] It was completely understood in two hepatocyte carcinoma cells lines, hepa-1 wild-type (c1c7) and the subunit mutated (c4) lacking hypoxia inducible factor-1 (HIF-1) that they are very susceptible to apoptosis by HGF. [104][105][106][107] Tumour biology reveals that there are two most important signal transduction pathways for c-Met ⁄ HGF multifunctional effects, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K).…”

“…113,114 However, apoptotic effects of HGF ⁄ c-Met is not yet fully understood, but it has been observed in number of cell lines such as ovarian carcinoma cell, breast carcinoma cell, mouse sarcoma cell, and mouse hepatocarcinoma cell. [115][116][117][118] It was completely understood in two hepatocyte carcinoma cells lines, hepa-1 wild-type (c1c7) and the subunit mutated (c4) lacking hypoxia inducible factor-1 (HIF-1) that they are very susceptible to apoptosis by HGF. In this case, p53, c-Myc progressively decreased, whereas, JNK1, caspase8, cytochrome c, and caspase 3 levels, are increased.…”