RESUMEN
Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.
Asunto(s)
Adenosilmetionina Descarboxilasa/metabolismo , Complejos Multiproteicos/metabolismo , Poliaminas/metabolismo , Neoplasias de la Próstata/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Adenosilmetionina Descarboxilasa/inmunología , Animales , Proliferación Celular , Activación Enzimática , Everolimus/uso terapéutico , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Metabolómica , Ratones , Complejos Multiproteicos/antagonistas & inhibidores , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Estabilidad Proteica , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
We purified AXC rat hepatic S-adenosyl-L-methionine decarboxylase (AMDC) 4900-fold and obtained a preparation that was 75% AMDC. This material caused elaboration of rabbit antirat AMDC antibodies that essentially were monoprecipitating. Antibody from one rabbit was highly effective as an inactivator of prostatic AMDC activity and was used to evaluate the quantitative relationship between antigenic mass and AMDC activity in ventral and dorsolateral prostates of young mature (185-day-old) and aged (776-day-old) AXC rats. Although AMDC activity of aged AXC rat prostates was diminished (ventral, 68%; dorsolateral, 50%), the quantities of antibody required to inactivate 1 U AMDC activity in prostates of young mature and aged rats were identical. This antibody effectively recognized enzymatically inactive AMDC, which is antigenically similar to active AMDC. Therefore, the age-related reductions in prostatic AMDC activity are not due to the production of so-called altered AMDC. Four days of exogenous testosterone treatment of aged AXC rats failed to enhance ventral prostate AMDC activity, whereas AMDC activity in dorsolateral prostates was elevated 2.3-fold. New AMDC activity was antigenically identical to that in dorsolateral prostates of untreated young mature or aged AXC rats. Because we previously established that age-related reductions in AXC rat prostatic AMDC activity are due to neither trivial causes nor enhanced inactivation, our present studies imply that reductions in AMDC activity are due to decreased prostatic AMDC content. These studies are an initial demonstration of senescence-related quantitative reductions in the prostatic content of AMDC molecules, which appear to represent altered expression of a specific androgen-responsive prostatic gene.
