Calmodulin in Neoplasia

An enhancement of CaM has been recognised as a feature of cell transformation and of malignant cells. CaM levels of human lung cancer cells are higher than that of benign tumours of the lung or normal lung tissue (Liu G.X. et al. 1996). These authors also describe a correlation between tumour grade and TNM stage and levels of CaM. However, Edelman et al. (1994) have described a CaM-like protein that is apparently restricted to epithelial cells. This CaM-like protein was identical in size and largely homologous to CaM, but, unlike CaM, its expression seems to be significantly lower in malignant cells.

The CaM antagonist J8 inhibits the invasive behaviour of the cutaneous melanoma cell line A-375SM and uveal melanoma cells (Dewhurst et al. 1997). Tamoxifen, its metabolites ,^-desmethyltamoxifen, and 17p-oestradiol also inhibit invasion in the absence of oestrogen receptors, which suggests that the inhibition produced by these anti-oestrogens was mediated by mechanisms other than receptor binding, e.g., CaM inhibition. A deregulation of intracellular calcium resulting in cell death is produced by tamoxifen at high concentrations where its effects are believed to be not mediated by oestrogen receptors (Jain and Trump, 1997).

CaM antagonists could inhibit invasion by starving the cytoskeletal machinery of local ATP generation. Glass-Marmor and Beitner (1997) found that the CaM inhibitors, which they had previously shown to reduce the levels of certain glycolytic enzymes and ATP and cause loss of viability (Glass-Marmor et al. 1996), also detach these enzymes from their association with the cytoskeleton.

It is possible that CaM could be influencing cell invasion by altering the expression of ECM-associated enzymes. Some years ago A. Ito et al. (1991) suggested that CaM could be differentially modulating the expression of TIMP and prometal-loproteinases 1 and 3 in fibroblasts derived from human cervical carcinoma. The expression of these enzymes is known to markedly alter the invasive behaviour of cancers (Sherbet and Lakshmi, 1997b). Possibly, therefore, modification of the expression of ECM-associated enzymes and the properties of the ECM as a means of modulating cell behaviour, ought to be seriously considered. S100A4 does seem to operate through such a mechanism (Merzak et al. 1994b; Lakshmi et al. 1997). It would seem, therefore, that CaM might involve more than one target enzyme in the modulation of invasive behaviour.

The Smoker's Sanctuary

The Smoker's Sanctuary

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