Graphical AbstractHighlights d Loss of PKCl/i promotes basal and NEPC features in vivo d PKCl/i represses mTORC1 activation through LAMTOR2 phosphorylation d Loss of PKCl/i increases the SGOCP through mTORC1/ATF4 to fuel DNA methylation d The mTORC1/ATF4/PHGDH axis is a synthetic vulnerability of NEPC SUMMARY Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)l/i is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCl/i deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

Graphical Abstract Highlights d HIF1a reduces intracellular aspartate levels d HIF1a impairs oxidative and reductive aspartate biosynthesis d The aspartate-generating GOT1 and GOT2 enzymes are repressed by HIF1a d Aspartate supplementation counteracts the antiproliferative influence of HIF1a In Brief Melé ndez-Rodríguez et al. show that HIF1a impairs oxidative and reductive aspartate biogenesis, which consequently drives HIF1a-dependent suppression of tumor cell proliferation. Mechanistically, HIF1a represses the aspartate-producing enzymes GOT1 and GOT2 in several biological settings, including human VHL-deficient renal cell carcinoma, in which HIF1a can act as a tumor suppressor.

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Extracellular signal-regulated kinase 5 (ERK5), also known as big mitogen-activated protein kinase (MAPK) 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL) gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas.

Bladder endometriosis is rare, although the bladder is the urinary tract structure most often affected by this condition. The common clinical manifestations of bladder endometriosis include menouria and urethral and pelvic pain syndrome occurring cyclically. Imaging methods are not conclusive for the definitive diagnosis. Cystoscopy is the most useful diagnostic test with confirmation by histologic study. Treatment must be individualized according to the patient's age, desire for future pregnancies, the severity of the symptoms, the site affected, and whether other organs are involved. Two types of treatment are currently used as follows: medical-hormonal and surgical.