ABSTRACT
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-P2. 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.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Receptors, Androgen , Animals , Humans , Male , Mice , Androgen Antagonists , Androgens/metabolism , Cell Line, Tumor , Mechanistic Target of Rapamycin Complex 1/metabolism , Prostatic Neoplasms, Castration-Resistant/metabolism , Receptors, Androgen/metabolism , Signal TransductionABSTRACT
Hypoxic-ischemic brain injury is the leading cause of disability and death after successful resuscitation from cardiac arrest, and, to date, no specific treatment option is available to prevent subsequent neurofunctional impairments. The hippocampal cornu ammonis segment 1 (CA1) is one of the brain areas most affected by hypoxia, and its degeneration is correlated with memory deficits in patients and corresponding animal models. The aim of this work was to evaluate the feasibility of neural progenitor cell (NPC) transplantation into the hippocampus in a refined rodent cardiac arrest model. Adult rats were subjected to 12 min of potassium-induced cardiac arrest and followed up to 6 weeks. Histological analysis showed extensive neuronal cell death specifically in the hippocampal CA1 segment, without any spontaneous regeneration. Neurofunctional assessment revealed transient memory deficits in ischemic animals compared to controls, detectable after 4 weeks, but not after 6 weeks. Using stereotactic surgery, embryonic NPCs were transplanted in a subset of animals 1 week after cardiac arrest and their survival, migration, and differentiation were assessed histologically. Transplanted cells showed a higher persistence in the CA1 segment of animals after ischemia. Glia in the damaged CA1 segment expressed the chemotactic factor stromal cell-derived factor 1 (SDF-1), while transplanted NPCs expressed its receptor CXC chemokine receptor 4 (CXCR4), suggesting that the SDF-1/CXCR4 pathway, known to be involved in the migration of neural stem cells toward injured brain regions, directs the observed retention of cells in the damaged area. Using immunostaining, we could demonstrate that transplanted cells differentiated into mature neurons. In conclusion, our data document the survival, persistence in the injured area, and neuronal differentiation of transplanted NPCs, and thus their potential to support brain regeneration after hypoxic-ischemic injury. This may represent an option worth further investigation to improve the outcome of patients after cardiac arrest.
