Overall, LXR activation in immune cells infiltrating the tumor mi

Overall, LXR activation in immune cells infiltrating the tumor microenvironment could induce a plethora of immune suppressive effects, ultimately leading to tumor growth. In this context, the development and use of isoform-specific find more antagonists could abrogate undesired effects and enhance the antitumor immune response [41]. As mentioned above, several LXR-independent tumor-promoting oxysterol effects have been identified. For example, tumor-derived oxysterols promote the migration of neutrophils

within tumor microenvironment [34] (Fig. 1E). Neutrophils recruited within the tumor microenvironment can exert protumor effects by promoting neo-angiogenesis and/or suppressing tumor-specific T cells (Fig. 1E) VX-770 datasheet [42]. This underscores the need to target not only LXRs, but also to target enzymes involved in oxysterol generation, or enzymes along the biosynthetic pathway of cholesterol downstream the Hydroxymethylglutaryl-CoA reductase, in order to abrogate LXR/LXR ligands signaling within the tumor microenvironment. Noteworthy, the inhibition of the Hydroxymethylglutaryl-CoA reductase inhibits the formation of the isoprenoids, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are involved in functional posttranslational modification (i.e., prenylation) of small GTPase proteins

including Rho, Rac, and CdC42 [43]. Failure of protein prenylation is in turn responsible for the altered functionality of immune cells, such as T cells and DCs [44]. In summary, oxysterols are able to affect several immune cells infiltrating tumor microenvironment. Dampening of immune cells can occur in an LXR-dependent and -independent manner. The abrogation of oxysterol production

as well as the use of specific LXR antagonists could be an effective strategy to restore antitumor responses and to potentiate the effects of new immunotherapeutics, recently introduced into clinical practice [45]. In contrast to the immune system-mediated effects of oxysterols, which generally seem to be tumor-promoting, oxysterols inhibit cancer cell proliferation, as demonstrated in vitro in a variety of human cancer cells, such Resveratrol as breast and colon cancer cells, T- and B-chronic lymphocytic leukemia (CLL), prostate and glioblastoma multiforme (GBM) cancer cells [41]. In some breast cancer cell lines, LXR activation leads to G1 to S-phase cell cycle arrest, through a mechanism that partly involves an ERα-dependent pathway, at least in tumor cell lines expressing and responding to ERα agonists [46]. Indeed, the activation of LXR through synthetic agonists induced the suppression of ERα at mRNA and protein levels [46]. LXR activation in these cell lines reduced the expression of S-phase kinase-associated protein 2 (Skp2), cyclin D1, and cyclin A2, and affected the phosphorylation state of retinoblastoma protein [46] (Fig. 2A). These findings established an initial molecular link between LXRs and cell cycle control.

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