RESUMEN
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)λ/ι 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 PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.
Asunto(s)
Carcinoma Neuroendocrino/patología , Regulación hacia Abajo , Isoenzimas/deficiencia , Neoplasias de la Próstata/patología , Proteína Quinasa C/deficiencia , Serina/metabolismo , Factor de Transcripción Activador 4/metabolismo , Vías Biosintéticas , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/metabolismo , Línea Celular Tumoral , Metilación de ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , S-Adenosilmetionina/metabolismoRESUMEN
The authors present a case of multiple radiation-induced cavernous malformations of the cauda equina in a patient with a remote history of testicular cancer and extended field radiation therapy. Magnetic resonance imaging (MRI) demonstrated multiple nodular areas of enhancement coating the nerve roots of the cauda equina, mimicking an aggressive leptomeningeal process such as carcinomatous or infectious meningitis. Biopsy of one of these lesions revealed ectatic vascular channels devoid of intervening neuroglial tissue consistent with cavernous malformation.
