Cancer cells and transformed cells undergo apoptosis when exposed to tumour necrosis factor (TNF). The TNF family of apoptosis-inducing factors include TRAIL, which is A TNF-related apoptosis inducing ligand. TRAIL is a type II integral membrane protein (Wiley et al., 1995; Pitti et al., 1996) and bears a high degree of homology to the Fas ligand, FasL (Nagata, 1997). TRAIL induces apoptosis of cells by binding to specific receptors. Binding of TRAIL to two receptors calledTRAIL-R1 and R2 appears to induce apoptosis, whereas binding of the ligand to TRAIL-R3 and R4 seem to inhibit apoptosis by acting as decoy receptors or by activating NF-kB. R1 and R2 possess the so-called death domains in the cytoplasmic tail whilst R3 and R4 lack these death domains (Degli-Esposti, Dougallo et al., 1997; Pan, Ni et al., 1997; Pan, O'Rourke et al.,
Angiogenesis signals ErbB2/B3/EGFr PDGF IL-6
Angiogenesis signals ErbB2/B3/EGFr PDGF IL-6
Figure 8 Signalling pathway involving phosphoinositide-3 kinase and Akt in the regulation of cell proliferation and apoptosis. The Figure shows the PI-3 kinase/Akt pathway of transduction of signals transduced via erbB family of receptors erbB2/B3/B4 and EGFr, PDGF, TNF, Fas, PTEN, TCL1 and TGFa leading to the regulation of cell proliferation and survival as well as to the acquisition of cell motility or invasive properties in the context of cancer cells. PI-3 kinase activates Akt as indicated by the inhibition of Akt activation by PI-3 kinase inhibitors. The downstream event following Akt activation is interaction of Akt with and activation of appropriate transcription factors and the modulation of expression of responsive genes (see Table 11). Akt activation results in the protection of cells from apoptosis, which by all accounts seems to be due to inactivation or reduction in the activity of caspases. Angiogenic signal transduction also follows the PI-3 kinase/Akt pathway resulting the regulation of VEGF expression. VEGF increases the permeability of endothelial cells and their proliferation and migration, and this seems to be due to the synthesis of nitric oxide synthase (NOS) (Yiyu et al., 1999), which is activated by Akt-mediated phosphorylation (Fulton el al., 1999). Inhibitors of NOS, PI-3 and MAPK inhibit VEGF-induced vascular permeability (Lai et at., 2001). Akt-mediated modulation of invasive behaviour of cancer cells can be attributed to its being targeted to the plasma membrane and its apparent involvement in the remodelling of the extracellular matrix. The interaction and mutual regulation of signalling pathways is illustrated in Figures 9 and 10. (MAPK, MAP kinase; NOS, nitric oxide synthase; PI3, phosphoinoside-3; TGF, transforming growth factor; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.) Based on references cited in the text and Blancher et al. (2001); Chaudhary and Hruska (2001); Choudhury (2001); Hatano and Brenner (2001); Hermanto et al. (2001); Okano et al. (2000); Shin et al. (2001); Wei et al. (2001).
1997). Osteoprotegerin is a fifth receptor. This competitively inhibits the binding of TRAIL to R1 and R2 receptors and in this way it seems to inhibit TRAIL-induced apoptosis (Emery etal., 1998). The differential expression of the pro- and anti-apoptosis receptors of TRAIL could be the reason why tumour cells are generally prone to induction of apoptosis by TRAIL whilst normal cells are not susceptible. Prostate cancer cells that are resistant to the apoptotic effect of TRAIL express Akt at constitutively high levels. Sensitivity to apoptosis is restored when Akt is downregulated by treatment with inhibitors of Akt (Thakkar et al., 2001). Hatano and Brenner (2001) recently confirmed the involvement of the PI3-kinase/Akt in the transduction of apoptosis signals by TNF-a and another member of theTNF family, namely Fas protein. Interestingly, TRAIL-R3 is a glycosyl-PI-3 linked receptor (Degli-Esposti, Smolak et al, 1997). Therefore it seems reasonable to conclude that theTNF family cytokine-induced apoptosis is controlled by the PI3-kinase/Akt. Downstream of the activation by phosphorylation of Akt by PI-3 kinase pathway are the caspases whose activity is reduced or inhibited by activated Akt, which in turn leads to protection of cells from apoptosis.
The induction of apoptosis by staurosporine as well as by etoposide, both well-established mitochondrial apoptotic stimuli, is accompanied by marked activation of Akt prior to the onset of apoptosis, and the resultant overexpression of Akt indeed greatly delays apoptosis (Tang et. al., 2001). It is to be expected that deregulation of the restraint on apoptosis would lead to tumour expansion and this has turned out to be the case. Akt is over-expressed in cancers of the thyroid (Ringel et al., 2001). Akt is said to be constitutively active in non-small cell lung carcinoma cells lines (Brognard etal., 2001). Its activation occurs upon exposure of breast cancer cell lines to oestrogen, irrespective of their ER status (Tsai et al., 2001). Zinda et al. (2001) found no differences in Akt RNA expression of normal and tumour tissues derived from lung, breast, prostate and colon. However, one ought to take cognisance of the possibility that there might yet be differences in protein expression due to regulation at the translational level. At the experimental level, Mende et al. (2001) were able to induce lymphomas in transgenic mice carrying the Akt gene controlled by the Ick promoter.
There is general acceptance that oncogenic stimuli frequently change the adhesive and motile properties of cells, often by bringing about the targeting of downstream effector molecules to the plasma membrane and by remodelling the extracellular matrix. It is therefore of much interest to note in the context of the behaviour of cancer the apparent relationship of Akt to cell motility flowing from a modulation of the structure of the extracellular matrix. Matrix metalloproteinases (MMP) and their inhibitors are among ECM components whose modulation is frequently associated with changes in invasive ability of cancer cells. XF Kim et al. (2001) found that Akt was localised at the leading plasma membrane edge of migrating cells. They have attributed the perceived promotion of migratory behaviour to an increased expression of MMP-9- Park et al. (2001) have confirmed not only that Akt enhances the invasive ability of cells but it also induces MMP-2. Possibly the targeting of Akt to the plasma correlates with changes in ECM composition together with acquisition of motility. Consistent with this Akt is translocated to the plasma membrane in the transduction of erbB2/erbB3 signal (Hellyer et al., 2001). According to Mende et al. (2001), myristoylation of Akt enhanced both its oncogenic property and kinase activity. In the context of Akt localisation this indicates that myristoylation might play a key role in the targeting of Akt to the cell membrane.
Besides MMPs, there are specific key proteins, which are closely involved with intercellular adhesion and invasive properties of the cancer cell. Notable among them are fibronectin, laminin and collagen type IV Li et al. (2001) found that activated Akt not only was targeted to the plasma membrane but it also induced the synthesis of laminin and collagen IV.
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