Lipid levels within the cells appear to have a role in oncogenesis and inhibition of lipogenic enzymes (such as fatty acid synthase and acetyl-CoA carboxylase) is able to counteract growth of different tumors (Johnson D.L et al. Trends Endocrinol Metab.2016). To date, lipid accumulation and modifications have not been extensively investigated as potential cancer prognostic factors or therapeutic targets in various cancers.
Autophagy, a highly conserved mechanism originally described in yeast, allows the turnover of cellular components and damaged organelles through double-membrane vesicles called autophagosomes, which fuse with lysosomes enabling autophagic substrates degradation by lysosomal enzymes and monomeric units recycle (Liu S et al., Comp Biochem Physiol A Mol Integr Physiol. 2010). Recently the ability of autophagy to mobilize intracellular lipid stores has been described, indicating autophagy modulation as an eligible way to control the amount and the quality of lipids in cancer cells, and several autophagic modulators are already being used in cancer clinical trials. Here, we propose to assess lipidomic networks and changes in the expression of lipid-related and/or autophagy genes in different tumor cell lines (prostate, breast and melanoma cancer cell lines). Moreover, we will evaluate the hypothesis that autophagy modulation might affect lipid composition counteracting tumor growth.
Lipid metabolites may contribute to several aspects of tumor biology, due to their deep involvement in several biological roles:
-they function as building blocks for biological membranes to support the high proliferative rate of cancer cells;
-intermediates of de novo lipogenesis, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid and sphingosine 1-phosphate function as second messengers in signal transduction pathways and are involved in crucial aspects of cell to cell communication;
-lipid-mediated post-translational modification of proteins is a vital process in regulating expression, localization and function of various signaling proteins (Zadra G et al., BBA 2013).
Our proposal aims at adding new insights on lipid accumulation and modifications in three types of cancer and on the correlation between autophagy and lipid profile.
Autophagy is a double-edged sword in cancer since tumor cells may activate autophagy to promote their survival in an environment where there is increased metabolic stress. Autophagy inhibition may be therefore an useful treatment route in terms of anti-cancer therapies and may be therapeutically beneficial sensitizing some cancer cell types to different chemotherapies. Alternatively, autophagy may act as a tumor suppressor as has been suggested by the observation that autophagic gene beclin1 deletion occurs in many PCas .
Investigating autophagy-regulated lipidomic networks along with gene array profiles of lipid-related genes will allow to underline novel roles for autophagy in cancer growth, defining novel correlations between lipidogenesis and cancer cell phenotype. We believe that this study might open new avenues in the identification of key lipid-related modifications affecting cell behaviour and therefore eligible as potential prognostic and/or therapeutic targets. It will also help to define if accurate pharmacological autophagy modulation might affect the storage of cholesteryl ester and of other lipid metabolites thus affecting tumor cell biology.