Phthalates represent a group of substances used in industry that have antiandrogenic activity and are found in different concentrations in human urine and plasma. More than 8 million tons of phthalates are used each year, predominantly as plasticizers in polyvinyl chloride (PVC) products. Phthalates are widely used in everyday consumer products and improperly discarded into the environment. Furthermore, in vivo studies carried out in our laboratory showed that a mixture of phthalates, equivalent to the mixture used in this study, deregulated the expression of genes and miRNAs associated with prostatic carcinogenic pathways. Thus, this study was designed to establish an in vitro model to assess pathways related to cell survival, proliferation, apoptosis, and biosynthesis of miRNAs, using both normal and tumoral prostatic epithelial cells exposed to an environmentally relevant mixture of phthalate metabolites.Tumor (LNCaP) and normal (PNT-2) prostatic epithelial cell lines were exposed for 24 and 72 h to vehicle control or the phthalate mixture. The selected metabolite mixture (1000 μmol/L) consisted of 36.7% monoethyl phthalate (MEP), 19.4% mono (2-ethylhexyl) phthalate (MEHP), 15.3% monobutyl phthalate (MBP), 10.2% monoisobutyl phthalate (MiBP), 10.2% monoisononyl phthalate (MiNP), and 8.2% monobenzyl phthalate (MBzP). Gene expression was performed by qRT-PCR and cell migratory potential was measured using cell migration assays. Our results showed that the mixture of phthalates increased cell turnover, oxidative stress, biosynthesis, and expression of miRNAs in LNCaP cells; thus, increasing their cellular expansive and migratory potential and modulating tumor behavior, making them possibly more aggressive.However, these effects were less pronounced in benign cells, demonstrating that, in the short term, benign cells are able to develop effective mechanisms or more resistance against the insult.

Colorectal cancer affects the large intestine, leading to loss of white adipose tissue (WAT) and alterations in adipokine secretion. Lower incidence of colorectal cancer is associated with increased fibre intake. Fructooligosaccharides (FOS) are fibres that increase production of butyrate by the intestinal microbiota. Tributyrin, a prodrug of butyric acid, exerts beneficial anti-inflammatory effects on colorectal cancer. Our aim was to characterise the effects of diets rich in FOS and tributyrin within the context of a colon carcinogenesis model, and characterise possible support of tumorigenesis by WAT. C57/BL6 male mice were divided into four groups: a control group (CT) fed with chow diet and three colon carcinogenesis-induced groups fed either with chow diet (CA), tributyrin-supplemented diet (BUT), or with FOS-supplemented diet. Colon carcinogenesis decreased adipose mass in subcutaneous, epididymal, and retroperitoneal tissues, while also reducing serum glucose and leptin concentrations. However, it did not alter the concentrations of adiponectin, interleukin (IL)-6, IL-10, and tumour necrosis factor alpha (TNF)-α in WAT. Additionally, the supplements did not revert the colon cancer affected parameters. The BUT group exhibited even higher glucose tolerance and levels of IL-6, VEGF, and TNF-α in WAT. To conclude our study, FOS and butyrate supplements were not beneficial. In addition, butyrate worsened adipose tissue inflammation.

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Phosphatidylinositol (PI)regulating enzymes are frequently altered in cancer and have become a focus for drug development. Here, we explore the phosphatidylinositol-5-phosphate 4-kinases (PI5P4K), a family of lipid kinases that regulate pools of intracellular PI, and demonstrate that the PI5P4Kα isoform influences androgen receptor (AR) signaling, which supports prostate cancer (PCa) cell survival. The regulation of PI becomes increasingly important in the setting of metabolic stress adaptation of PCa during androgen deprivation (AD), as we show that AD influences PI abundance and enhances intracellular pools of PI-4,5-P 2 . We suggest that this PI5P4Kα-AR relationship is mitigated through mTORC1 dysregulation and show that PI5P4Kα colocalizes to the lysosome, the intracellular site of mTORC1 complex activation. Notably, this relationship becomes prominent in mouse prostate tissue following surgical castration. Finally, multiple PCa cell models demonstrate marked survival vulnerability following stable PI5P4Kα inhibition. These results nominate PI5P4Kα as a target to disrupt PCa metabolic adaptation to castrate resistance.