RESUMO
Argininosuccinate synthase (ASS1), a critical enzyme in the urea cycle, acts as a tumor suppressor in many cancers. To date, the anticancer mechanism of ASS1 has not been fully elucidated. Here, we found that phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in serine synthesis, is a pivotal protein that interacts with ASS1. Our results showed that ASS1 directly binds to PHGDH and promotes its ubiquitination-mediated degradation to inhibit serine synthesis, consequently suppressing tumorigenesis. Importantly, the tumor suppressive effects of ASS1 were strongly abrogated by PHGDH knockout. In addition, ASS1 knockout and knockdown partially rescued cell proliferation when serine and glycine were depleted, while the inhibitory effect of ASS1 overexpression on cell proliferation was restored by the addition of serine and glycine. These findings unveil a novel role of ASS1 and suggest that the ASS1/PHGDH serine synthesis pathway is a promising target for cancer therapy.
Assuntos
Argininossuccinato Sintase , Proliferação de Células , Fosfoglicerato Desidrogenase , Serina , Neoplasias de Mama Triplo Negativas , Fosfoglicerato Desidrogenase/metabolismo , Fosfoglicerato Desidrogenase/genética , Serina/metabolismo , Serina/biossíntese , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/genética , Animais , Argininossuccinato Sintase/metabolismo , Argininossuccinato Sintase/genética , Linhagem Celular Tumoral , Camundongos Nus , Ubiquitinação , Camundongos , Glicina/metabolismoRESUMO
Hofmeister series (HS), ion specific effect, or lyotropic sequence acts as a pivotal part in a number of biological and physicochemical phenomena, e.g., changing the solubility of hydrophobic solutes, the cloud points of polymers and nonionic surfactants, the activities of various enzymes, the action of ions on an ion-channel, and the surface tension of electrolyte solutions, etc. This review focused on how ion specificity influences the critical micelle concentration (CMC) and how the thermoresponsive behavior of surfactants, and the dynamic transition of the aggregate, controls the aggregate transition and gel formation and tunes the properties of air/water interfaces (Langmuir monolayer and interfacial free energy). Recent progress of the ion specific effect in bulk phase and at interfaces in amphiphilic systems and gels is summarized. Applications and a molecular level theoretical explanation of HS are discussed comprehensively. This review is aimed to supply a fresh and comprehensive understanding of Hofmiester phenomena in surfactants, polymers, colloids, and interface science and to provide a guideline to design the microstructures and templates for preparation of nanomaterials.