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Rôle du cholestérol et des récepteurs nucléaires LXRs dans le cancer de la prostate

Abstract : In the recent decades, increased consumption of carbohydrates, fatty acids and cholesterol, linked to changes in dietary habits in most industrialized countries, is the cause of various diseases such as obesity, cardio-vascular troubles, development of type II diabetes and the onset of cancer. Literature reveals several arguments suggesting that cholesterol may be a risk factor in the occurrence of prostate cancer. First, hypercholesterolemia has been associated with an increased incidence of prostate cancer and, second, cancer cells exhibit deregulations of lipid metabolism associated with cholesterol accumulation in solid tumors. The objectives of this work were to analyze the role of cholesterol in the development of prostate cancer and to study the role of nuclear receptors LXRs (liver X receptors), fundamental regulators of cholesterol homeostasis, in the mechanisms associated with tumor initiation and progression. Our results show that cholesterol overload induced by a diet in lxr knockout mice may initiate the early stages of tumor development by epigenetic mechanisms involving the repressive action of histone methyltransferase EZH2 on tumor suppressor genes. In parallel, the pharmacological activation of LXRs in human cancer cells reduced tumor growth by increasing cell death through mechanisms involving lipid rafts.Taken together, our data reveal the existence of a relationship between environmental factors such as diet consumption of cholesterol and changes of epigenetic imprinting, a mechanism increasingly associated with carcinogenic process. Our data also indicate that LXRs protect from the initiation and progression of prostate cancer by blocking the accumulation of intracellular cholesterol. Thus, all therapeutic strategies leading to intra-tumoral cholesterol lowering, such as pharmacological activation of LXRs, may be relevant treatments of prostate cancer.
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https://tel.archives-ouvertes.fr/tel-00703479
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Aurélien Pommier. Rôle du cholestérol et des récepteurs nucléaires LXRs dans le cancer de la prostate. Sciences agricoles. Université Blaise Pascal - Clermont-Ferrand II, 2010. Français. ⟨NNT : 2010CLF22078⟩. ⟨tel-00703479⟩

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