RESUMEN
Rationale: Hepatocellular carcinoma (HCC) is one of the most severe cancers worldwide, with few effective targeted therapies for HCC. Lipid metabolic reprogramming is emerged as a hallmark of cancer metabolism that guides response to antitumoral therapies. Such lipid metabolic alteration in cancers is critically regulated by the mammalian target of rapamycin mTOR, which is considered as a promising therapeutic target. Despite efforts, mTOR inhibitors (mTORi) have produced limited response clinically, partly due to incomplete knowledge of mTORC1 addiction in cancers. Methods: CRISPR-Cas9 system was used to establish Hpcal1 null mice. The liver cancer model in mice was generated using Hpcal1-deficient mice with diethylnitrosamine (DEN) /CCL4 or MYC/Trp53-/- via hydrodynamic tail-vein injection. RNA-sequencing (RNA-seq) was used to identify potential signaling pathways. The expression of HPCAL1 and mTOR signaling were determined using quantitative polymerase chain reaction (qPCR), western blot and immunohistochemistry. The role of Hpcal1 in liver tumorigenesis and its response to mTORi was assessed by CCK-8 measurements, colony formation assay and in mouse model. Results: In this study, we identified hippocalcin-like protein 1 (HPCAL1) as an important negative regulator of de novo lipid biosynthesis and mTOR signaling activation, limiting liver tumorigenesis and establishing a metabolic vulnerability of HCC in mice. Genetic loss of HPCAL1 rendered HCC mTORC1-addicted and sensitive to mTORi AZD-8055 in vitro and in vivo. Importantly, HPCAL1 expression was inversely correlated with the levels of mTOR phosphorylation and several critical lipid biosynthesis enzymes in human specimens. Mechanistically, HPCAL1 directly bound to RuvB Like AAA ATPase 1 (RUVBL1), inhibiting the assembly of TEL2-TTI1-TTI2 (TTT)-RUVBL complex and subsequent leading the mTOR signaling suppression. Conclusion: We uncover a metabolic vulnerability and mTOR addiction in HCC with HPCAL1 loss that provides a selective therapeutic window for HCC with mTORC1 hyperactivation using mTORi.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Humanos , Ratones , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Carcinogénesis , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Proteínas Portadoras/metabolismo , Transformación Celular Neoplásica , ADN Helicasas/metabolismo , Hipocalcina/metabolismo , Metabolismo de los Lípidos , Lípidos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Mamíferos/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Gastric cancer (GC) is one of the most severe gastric diseases worldwide. However, the molecular basis that drives tumorigenesis and progression is not completely understood, which hinders the efficacy and development of therapeutic options. Glutathione-S-transferases (GSTs) are a group of phase II detoxification enzymes that maintain redox homeostasis; however, their roles in cancers are not well defined. Here, we revealed that the expression of GST family members is significantly impaired in GC tissues. Glutathione-S-transferase mu 3 (GSTM3), a member of GST family, is dramatically downregulated in cancerous tissues and has been identified as an independent prognostic factor in GC associated with tumor differentiation, inhibiting GC cell proliferation and migration in vitro and in vivo. Mechanistically, GSTM3 is transcriptionally activated by NRF2/KEAP1 signaling. As a feedback loop, GSTM3 binds to Cullin-associated and neddylation-dissociated 1 protein (CAND1), an exchange factor for integrating Kelch-like ECH-associated protein 1 (KEAP1) into Cul3-RING ubiquitin ligases (CRL3), to disrupt nuclear factor-erythroid factor 2-related factor 2 (NRF2)/KEAP1 binding and prevent NRF2 ubiquitination and degradation, leading to its activation. A deficiency in glutathione S-Transferase Mu 3 (GSTM3) reduces DNA mismatch repair (MMR) gene expression and increases mutagenesis via CAND1/NRF2 binding. Importantly, GSTM3/NRF2 and KEAP1 were negatively and positively associated with the genomic signature for microsatellite instability, respectively. Clinically, GSTM3, NRF2, and MutS homolog 6 (MSH6) were positively correlated in the GC specimens. This study uncovered a reciprocal regulation between GSTM3 and NRF2 and established a functional and clinical link between GSTM3-NRF2/KEAP1 and MMR during GC cell proliferation and progression, thus providing potential therapeutic targets for GC.
Asunto(s)
Proteínas Cullin , Factor 2 Relacionado con NF-E2 , Carcinogénesis/genética , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Reparación de la Incompatibilidad de ADN , Glutatión/metabolismo , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factores de TranscripciónRESUMEN
BACKGROUND AND OBJECTIVES: The severity of neurologic impairment is significantly associated with gastrointestinal (GI) hemorrhage. Therefore, the aim of this study was to compare the effect of two nutritional interventions in acute ischemic stroke patients with GI hemorrhage. METHODS AND STUDY DESIGN: We retrospectively studied consecutive ischemic stroke patients with GI hemorrhage from January 2014 to December 2018. They were stratified into two programs of nutritional therapy after GI hemorrhage: moderate feeding (more than 70% optimal caloric uptake, 50-100 mL/h) and trophic feeding (16-25% of the target energy expenditure, 25 kcal/kg per day, 10- 30 mL/h) with supplemental parenteral nutrition. RESULTS: The group receiving moderate feeding included 30 patients, and the group receiving trophic feeding and supplemental parenteral nutrition included 32 patients. There was no statistically significant difference between the two groups in the baseline characteristics of the patients. Mortality, Glasgow Coma Scale (GCS) score at discharge, and Glasgow Outcome Scale (GOS) score 3 months after discharge were compared between the two groups. In the moderate feeding group, the overall mortality was significantly lower than in the trophic feeding and supplemental parenteral nutrition group (p<0.05). Conscious state and neurological severity were assessed by the GCS score before discharge, and the score was higher in the moderate feeding group than in the other group (p<0.05). The GOS score 3 months after discharge was higher in the moderate feeding group than in the trophic feeding and supplemental parenteral nutrition group (p<0.05). These three items showed that moderate feeding led to a better prognosis: lower occurrence of mortality, higher GCS score at discharge, and higher GOS score 3 months after discharge. CONCLUSIONS: This study showed that moderate feeding had a much more profound effect on the outcomes than trophic feeding and supplemental parenteral nutrition, as it was associated with lower mortality, higher GCS score at discharge, and higher GOS score 3 months after discharge.