THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer.

Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.

Sigma-1 (σ1) receptor activity is necessary for physiological brain plasticity in mice.

The sigma-1 receptor (S1R) is a membrane-associated protein expressed in neurons and glia at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs). S1R interacts with different partners to regulate cellular responses, including ER stress, mitochondrial physiology and Ca2+ fluxes. S1R shapes cellular plasticity by directly modulating signaling pathways involved in inflammatory responses, cell survival and death. We here analyzed its impact on brain plasticity in vivo, in mice trained in a complex maze, the Hamlet test. The device, providing strong enriched environment (EE) conditions, mimics a small village. It has a central agora and streets expanding from it, leading to functionalized houses where animals can Drink, Eat, Hide, Run, or Interact. Animals were trained in groups, 4 h/day for two weeks, and their maze exploration and topographic memory could be analyzed. Several groups of mice were considered: non-trained vs. trained; repeatedly administered with saline vs. NE-100, a selective S1R antagonist; and wildtype vs. S1R KO mice. S1R inactivation altered maze exploration and prevented topographic learning. EE induced a strong plasticity measured through resilience to behavioral despair or to the amnesic effects of scopolamine, and increases in S1R expression and bdnf mRNA levels in the hippocampus; increases in neurogenesis (proliferation and maturation); and increases of histone acetylation in the hippocampus and cortex. S1R inactivation altered all these parameters significantly, showing that S1R activity plays a major role in physiological brain plasticity. As S1R is a major resident protein in MAMs, modulating ER responses and mitochondrial homeostasy, MAM physiology appeared impacted by enriched environment.