Oxysterols in cancer cell proliferation and death
2013
de Weille, Jan | Fabre, Christine | Bakalara, Norbert
Oxysterols have been shown to interfere with proliferation and cause the death of many cancer cell types, such as leukaemia, glioblastoma, colon, breast and prostate cancer cells, while they have little or no effect on senescent cells. The mechanisms by which oxysterols may influence proliferation are manifold: they control the transcription and the turnover of the key enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase, by binding to Insig-1, Insig-2 and liver X receptors. Oxysterols are thought to be generated in proportion to the rate of cholesterol synthesis. Although there is no consensus about the mechanism by which these oxysterols are generated in vivo, it clearly has to be ubiquitous. The 25- and the 27-cholesterol hydroxylases, present in almost all tissues, are possible candidates. Cholesterol uptake from lipoproteins, intracellular vesicle transport and lipid transfer are also modified by oxysterols. Oxysterols interfere with ERK, hedgehog and wnt pathways of proliferation and differentiation. When administered in vitro to cancer cell lines, oxysterols invariably both slow down proliferation and provoke cell death. Perhaps is it sufficient to stop proliferation of a cancer to provoke its eradication. Therefore, the two facets of oxysterol action that seem important for cancer treatment, cytostaticity and cytotoxicity, will be discussed.
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