Long-Term Fenofibrate Treatment Stimulates the Phenotypic Microevolution of Prostate Cancer Cells In Vitro.

Fenofibrate is a widely used anti-hyperlipidemic agonist of peroxisome proliferator-activated receptor alpha (PPARα). As a metabolic blocker, fenofibrate interferes with cancer promotion/progression via its misbalancing effects on cellular metabolism. However, the consequences of its long-term application for patients with diagnosed drug-resistant cancers are unknown. We addressed this point by tracing the phenotypic microevolution of naïve and drug-resistant prostate cancer PC3_DCX20 cells that underwent a long-term exposition to 10 µM and 50 µM fenofibrate. Their resistance to fenofibrate, metabolic profile and invasive phenotype were estimated in the control conditions and under fenofibrate-induced stress. Apparently, drug efflux systems are not effective against the cytostatic FF action. However, wtPC3 and PC3_DCX20 cells that survived the long-term 50 µM fenofibrate treatment gave rise to lineages that displayed an increased proliferation rate, lower motility in the control conditions and enhanced fenofibrate resistance. Attenuated fenofibrate bioavailability modified the pattern of PC3 microevolution, as illustrated by phenotypic differences between wtPC3/PC3_DCX20 lineages propagated in the presence of 50 µM and 10 µM fenofibrate. Collectively, our observations indicate that fenofibrate acts as a selective factor that affects prostate cancer microevolution. We also pinpoint potential consequences of long-term exposition of prostate cancer patients to metabolic blockers.

Glial expression of DmMANF is required for the regulation of activity, sleep and circadian rhythms in the visual system of Drosophila melanogaster.

DmMANF, Drosophila melanogaster mesencephalic astrocyte-derived neurotrophic factor (DmMANF) is an evolutionarily conserved orthologue of mammalian MANF. This neurotrophic factor exerts many functions in the Drosophila brain, particularly those dependent on glial cells. As we found in our earlier study, downregulation of DmMANF in glia induces degeneration of glial cells in the first optic neuropil (lamina) where DmMANF abundance is especially high. In the present study, we observed that changes in the level of DmMANF in two types of glia, astrocyte-like glia (AlGl) and ensheathing glia (EnGl), affect activity and sleep of flies. Interestingly, a proper level of DmMANF in AlGl seems to be important in guiding processes of pigment dispersing factor (PDF)-expressing clock neurons. This is supported by our finding that DmMANF overexpression in AlGl leads to structural changes in the architecture of the PDF-positive arborization in the brain. Finally, we detected that DmMANF also affects rhythms in glia themselves, as circadian oscillations in expression of the catalytic α subunit of the sodium pump in the lamina epithelial glia were abolished after DmMANF silencing. DmMANF expressed in AlGl and EnGl seems to affect the activity of neurons leading to changes in behaviour.