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.

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.

Prostate cancer (PCa) is the second most common cancer and the second leading cause of cancer-related mortality among men. Gene expression analysis has been crucial in understanding tumor biology and providing disease progression markers. Cell surface glycoproteins and those in the extracellular matrix play significant roles in the PCa microenvironment by promoting migration, invasion, and metastasis. The molecular and histopathological heterogeneity of prostate tumors necessitates a new marker discovery to better stratify patients at risk for poor prognosis. In this study, our objectives were to investigate and characterize the localization and expression of SLIT/ROBO in PCa samples from transgenic mice and human tumor samples, aiming to identify novel prognostic markers and potential therapeutic targets. We conducted histopathological, immunohistochemical, and bioinformatics analyses on prostate tumors from two knockout mice models (Pb-Cre4/Pten^f/f and Pb-Cre4/Trp53^f/f;Rb1^f/f) and human prostate tumors. Transcriptomic analyses revealed special changes in the expression of genes related to the SLIT/ROBO neural signaling pathway. We further characterized the gene and protein expression of the SLIT/ROBO pathway in knockout animal samples, and protein expression in the PCa samples of patients with different Gleason scores. Public datasets with clinical data from patients (The Human Protein Atlas, cBioPortal, SurvExpress and CamcAPP) were used to validate the gene and protein expression of SLIT1, SLIT2, ROBO1, and ROBO4, correlating these alterations with the prognosis of subgroups of patients. Our findings highlight potential biomarkers of the SLIT/ROBO pathway with prognostic and predictive value, as well as promising therapeutic targets for PCa.

Obesity significantly decreases life expectancy and increases the incidence of age-related dysfunctions, including β-cell dysregulation leading to inadequate insulin secretion. Here, we show that diluted plasma from obese human donors acutely impairs β-cell integrity and insulin secretion relative to plasma from lean subjects. Similar results were observed with diluted sera from obese rats fed ad libitum , when compared to sera from lean, calorically-restricted, animals. The damaging effects of obese circulating factors on β-cells occurs in the absence of nutrient overload, and mechanistically involves mitochondrial dysfunction, limiting glucose-supported oxidative phosphorylation and ATP production. We demonstrate that increased levels of adiponectin, as found in lean plasma, are the protective characteristic preserving β-cell function; indeed, sera from adiponectin knockout mice limits β-cell metabolic fluxes relative to controls. Furthermore, oxidative phosphorylation and glucose-sensitive insulin secretion, which are completely abrogated in the absence of this hormone, are restored by the presence of adiponectin alone, surprisingly even in the absence of other serological components, for both the insulin-secreting INS1 cell line and primary islets. The addition of adiponectin to cells treated with plasma from obese donors completely restored β-cell functional integrity, indicating the lack of this hormone was causative of the dysfunction. Overall, our results demonstrate that low circulating adiponectin is a key damaging element for β-cells, and suggest strong therapeutic potential for the modulation of the adiponectin signaling pathway in the prevention of age-related β-cell dysfunction. Abstract Figure: Graphical Incubation of β-cells with sera or plasma from obese rats and humans hampers mitochondrial oxidative phosphorylation and glucose-stimulated insulin secretion (GSIS) relative to sera and plasma from lean rats and humans. Adiponectin, found at elevated levels in lean subjects, supports β-cell function on its own, in the absence of sera, and also reverses the effects of obese plasma. Prepared using Biorender.com.