RESUMO
Cancer cells have high demands for non-essential amino acids (NEAAs), which are precursors for anabolic and antioxidant pathways that support cell survival and proliferation. It is well-established that cancer cells consume the NEAA cysteine, and that cysteine deprivation can induce cell death; however, the specific factors governing acute sensitivity to cysteine starvation are poorly characterized. Here, we show that that neither expression of enzymes for cysteine synthesis nor availability of the primary precursor methionine correlated with acute sensitivity to cysteine starvation. We observed a strong correlation between efflux of the methionine-derived metabolite methylthioadenosine (MTA) and sensitivity to cysteine starvation. MTA efflux results from genetic deletion of methylthioadenosine phosphorylase (MTAP), which is frequently deleted in cancers. We show that MTAP loss upregulates polyamine metabolism which, concurrently with cysteine withdrawal, promotes elevated reactive oxygen species and prevents cell survival. Our results reveal an unexplored metabolic weakness at the intersection of polyamine and cysteine metabolism.
Assuntos
Cisteína/metabolismo , Redes e Vias Metabólicas , Neoplasias/metabolismo , Poliaminas/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Cisteína/deficiência , Feminino , Técnicas de Inativação de Genes , Humanos , Metionina/metabolismo , Camundongos , Purina-Núcleosídeo Fosforilase/genética , Purina-Núcleosídeo Fosforilase/metabolismo , Espécies Reativas de Oxigênio , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The control of systemic metabolic homeostasis involves complex inter-tissue programs that coordinate energy production, storage, and consumption, to maintain organismal fitness upon environmental challenges. The mechanisms driving such programs are largely unknown. Here, we show that enteroendocrine cells in the adult Drosophila intestine respond to nutrients by secreting the hormone Bursicon α, which signals via its neuronal receptor DLgr2. Bursicon α/DLgr2 regulate energy metabolism through a neuronal relay leading to the restriction of glucagon-like, adipokinetic hormone (AKH) production by the corpora cardiaca and subsequent modulation of AKH receptor signaling within the adipose tissue. Impaired Bursicon α/DLgr2 signaling leads to exacerbated glucose oxidation and depletion of energy stores with consequent reduced organismal resistance to nutrient restrictive conditions. Altogether, our work reveals an intestinal/neuronal/adipose tissue inter-organ communication network that is essential to restrict the use of energy and that may provide insights into the physiopathology of endocrine-regulated metabolic homeostasis.
Assuntos
Tecido Adiposo/metabolismo , Drosophila melanogaster/metabolismo , Células Enteroendócrinas/metabolismo , Intestinos/citologia , Hormônios de Invertebrado/metabolismo , Neurônios/metabolismo , Animais , Proteínas de Drosophila/metabolismo , Metabolismo Energético , Células Enteroendócrinas/citologia , Feminino , Glucose/metabolismo , Homeostase , Hormônios de Inseto/metabolismo , Nutrientes/metabolismo , Oligopeptídeos/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/metabolismoRESUMO
Bursicon is the main regulator of post molting and post eclosion processes during arthropod development. The active Bursicon hormone is a heterodimer of Burs-α and Burs-ß. However, adult midguts express Burs-α to regulate the intestinal stem cell niche. Here, we examined the potential expression and function of its heterodimeric partner, Burs-ß in the adult midgut. Unexpectedly, our evidence suggests that Burs-ß is not significantly expressed in the adult midgut. burs-ß mutants displayed the characteristic developmental defects but showed wild type-like adult midguts, thus uncoupling the developmental and adult phenotypes seen in burs-α mutants. Gain of function data and ex vivo experiments using a cAMP biosensor, demonstrated that Burs-α is sufficient to drive stem cell quiescence and to activate dLGR2 in the adult midgut. Our evidence suggests that the post developmental transactivation of dLGR2 in the adult midgut is mediated by Burs-α and that the ß subunit of Bursicon is dispensable for these activities.
Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Trato Gastrointestinal/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Hormônios de Invertebrado/genética , Subunidades Proteicas/genética , Receptores Acoplados a Proteínas G/genética , Animais , AMP Cíclico/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Trato Gastrointestinal/crescimento & desenvolvimento , Hormônios de Invertebrado/metabolismo , Muda/genética , Fenótipo , Multimerização Proteica , Subunidades Proteicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Nicho de Células-Tronco/genética , Ativação TranscricionalRESUMO
p120ctn is a ubiquitously expressed core component of cadherin junctions and essential for vertebrate development. Surprisingly, Drosophila p120ctn (dp120ctn) is dispensable for adherens junctions and development, which has discouraged Drosophila researchers from further pursuing the biological role of dp120ctn. Here we demonstrate that dp120ctn loss results in increased heat shock sensitivity and reduced animal lifespan, which are completely rescued by ectopic expression of a dp120ctn-GFP transgene. Transcriptomic analysis revealed multiple relish/NF-κB target genes differentially expressed upon loss of dp120ctn. Importantly, this aberrant gene expression was rescued by overexpression of dp120ctn-GFP or heterozygosity for relish. Our results uncover a novel role for dp120ctn in the regulation of animal stress response and immune signalling. This may represent an ancient role of p120ctn and can influence further studies in Drosophila and mammals.