Deregulation Of Inositol 145trisphosphate Pathway And Its Consequences

It is hardly surprising that interference with signal transduction pathways and their deregulation should have serious consequences for biological responses in developmental systems as well as in pathogenesis. Ecdysone, a steroid hormone, regulates a variety of developmental processes and metamorphosis in insects. It also influences neuronal responses, apoptosis, and histiolysis in a variety of larval tissues, binds to nuclear receptors, which show tissue- and stage-specific expression (Kamimura et al. 1997); and regulates ecdysone-responsive genes (No et al. 1996; Truman, 1996). The metamorphic changes involve "early" and "late" genes, with the early genes encoding proteins that regulate the expression of late genes (Baehrecke, 1996). Although our knowledge of the mechanics of ecdysone signal transduction is still rudimentary, it is clear that the pathway involves calcium signalling. The prothorac-icotropic hormone (PTTH) stimulates the synthesis of ecdysone in the prothoracic gland of Galleria larvae (Birkenbeil, 1996). PTTH increased intracellular Ca2+ levels of prothoracic gland in vitro. This increase could be abolished by removing extracellular calcium and by calcium channel inhibitors. The PTTH-stimulated increase of intracellular calcium was not abolished by agents, which inhibit mobilisation of calcium from intracellular stores. Recently, Venkatesh and Hasan (1997) found that disruption of IP3 receptor gene function in Drosophila larvae grossly affected metamorphosis and ecdysone synthesis and secretion. They generated IP3R gene (itpr) mutants. The mutations delayed moulting and were lethal at early larval stages.

Feeding ecdysone to mutant larvae partially counteracted the phenotypic effects of the itpr mutation, and down-regulated ecdysone-inducible genes.

General or specific abnormalities of signal transduction pathways (e.g., occurrence of abnormalities in one or more components of the transduction pathway) may be associated with disease processes, including the invasive behaviour and metastatic progression of cancers. Such disruptions of the signal transduction cascade in human cancers has been studied by measuring the levels of three enzymes involved in the generation of IP3, namely, phosphatidylinositol 4-kinase, phosphatidyl 4-phosphate 5 kinase, and PLC. Weber et al. (1996) found that all three enzymes were up-regulated with tumour progression. In rat hepatomas the enzyme levels rose by two- to eight-fold compared with normal liver. A three- to four-fold increase in PIP kinase and PI kinase was found in ovarian epithelial cancers. Weber et al. (1996) found a dramatic 16- and 96-fold increase of these enzymes in human breast carcinoma cells compared with normal breast parenchy-mal cells. These changes clearly correlated with enhanced IP3 expression and proliferative potential. Further evidence has also been reported by Singhal et al. (1997), who investigated the connection between elevated IP3 and DAG with proliferation of the breast cancer cell line MDA-MB-435 and the ovarian cancer cell line OVCAR-5. They demonstrated that quercetin treatment of the cells inhibited PI kinase and reduced IP3 before any inhibition in cell proliferation was evident. The expression of these kinases seems to be up-regulated by differentiation-inducing agents. Thus Ai et al. (1995) found enhanced expression of PI kinase as well as IP3 in murine erythroleukaemia cells induced toward erythroid differentiation by dimethyl sulphoxide (DMSO) treatment.

Another line of circumstantial evidence may be cited. For instance, monoterpe-nes such as limonene and perillyl alcohol have been reported not only to prevent tumour initiation and promotion, but also to inhibit tumour progression. These monoterpenes appear to inhibit the isoprenylation of G-proteins (Gould, 1997), which are a component of the signal transduction machinery (Figure 5). Similarly, abnormalities in the related pathway involving DAG and PKC may also be associated with cancers, as demonstrated by Hoelting et al. (1997) using the PKC agonist TPA (12-0-tetradecanoyl phorbol 13-acetate). They reported a 15% increase in the invasive ability of a follicular thyroid cancer cell line. In contrast, PKC inhibitors such as staurosporine, chelerythrine and calphostin C reduced invasion by 62%. CAI which inhibits calcium influx into cells, has been reported to inhibit the proliferative and invasive capacity of cell lines derived from human prostate cancer (Wasilenko et al. 1996). The neuroendocrine cells of prostate cancer express bombesin and gastrin-releasing peptide (GRP). In vitro bombesin and GRP signals invoke cell proliferation via bombesin receptors of which there are three subtypes: GRP receptors (GRPr), neuromedin B receptor, and bombesin receptor subtype 3. Transcripts of GRPr only, but not neuromedin B or bombesin receptor subtype 3, have been found in androgen-insensitive prostate cancer cell lines PC-3 and DU-145, suggesting the very important role GRPr play in signal transduction in these cells (Aprikian et al. 1996). In all lines derived from advanced prostate cancer, several agents such as GRP, bombesin, and bradykinin, among others, raised intracellular calcium levels.

FIGURE 5 The cAMP/Ca2+-signalling pathway. The binding of extracellular ligands to specific receptors regulates adenylyl cyclase activity via the linking G-proteins. The cAMP generated activates protein kinases that phosphorylate substrate proteins. Another route starts with the raising of intracellular calcium levels, which in turn regulate adenylyl cyclase activity.

FIGURE 5 The cAMP/Ca2+-signalling pathway. The binding of extracellular ligands to specific receptors regulates adenylyl cyclase activity via the linking G-proteins. The cAMP generated activates protein kinases that phosphorylate substrate proteins. Another route starts with the raising of intracellular calcium levels, which in turn regulate adenylyl cyclase activity.

However, bombesin did not influence calcium levels of an immortalised prostate cell line (Wasilenko et al. 1997). The authors have, therefore, suggested not only that there might be multiple receptors that can mediate increases in intracellular calcium levels of androgen-independent prostate cancer cell lines, but also that GRPr expression may be associated with the progression of prostate cancer. Calcitonin-like peptides may also function as neuropeptides in prostate cancer. The peptide binds to high-affinity receptors in the plasma membrane and induces a rapid and marked increase in intracellular calcium. Furthermore, the calcitonin signal is transduced into a clear proliferative response. The pattern of calcium response is biphasic in the form of a spike, and plateau is regarded as indicative of the phospholipid/calcium-signalling system (Shah et al. 1994).

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