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1.
Oncogene ; 41(43): 4779-4794, 2022 10.
Article in English | MEDLINE | ID: mdl-36127398

ABSTRACT

Genetic alteration of Rho GTPase-activating proteins (ARHGAP) and GTPase RhoA is a hallmark of diffuse-type gastric cancer and elucidating its biological significance is critical to comprehensively understanding this malignancy. Here, we report that gene fusions of ARHGAP6/ARHGAP26 are frequent genetic events in peritoneally-metastasized gastric and pancreatic cancer. From the malignant ascites of patients, we established gastric cancer cell lines that spontaneously gain hotspot RHOA mutations or four different ARHGAP6/ARHGAP26 fusions. These alterations critically downregulate RhoA-ROCK-MLC2 signaling, which elicits cell death. Omics and functional analyses revealed that the downstream signaling initiates actin stress fibers and reinforces intercellular junctions via several types of catenin. E-cadherin-centered homotypic adhesion followed by lysosomal membrane permeabilization is a pivotal mechanism in cell death. These findings support the tumor-suppressive nature of ARHGAP-RhoA signaling and might indicate a new avenue of drug discovery against this refractory cancer.


Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Actins/metabolism , GTPase-Activating Proteins/genetics , GTPase-Activating Proteins/metabolism , Cadherins/metabolism , Catenins/metabolism , Cell Death , rhoA GTP-Binding Protein/genetics , rhoA GTP-Binding Protein/metabolism
2.
Sci Rep ; 9(1): 14627, 2019 10 10.
Article in English | MEDLINE | ID: mdl-31601997

ABSTRACT

Gastric cancer remains one of the leading causes of cancer death worldwide. Despite intensive investigations of treatments over the past three decades, the poor prognosis of patients with unresectable advanced or recurrent gastric cancer has not significantly changed, and improved therapies are required. Here, we report the identification of an oncogenic mutation in FGFR4 in a human gastric tumour that leads to constitutive activation of its product, FGFR4. The G636C-FGFR4 tyrosine kinase domain mutation was found in 1 of 83 primary human gastric tumours. The G636C mutation increased FGFR4 autophosphorylation, and activated FGFR4 downstream signalling molecules and enhanced anchorage-independent cell growth when expressed in NIH/3T3 cells. 3D-structural analysis and modelling of FGFR4 suggest that G636C destabilizes an auto-inhibitory conformation and stabilizes an active conformation, leading to increased kinase activation. Ba/F3 cell lines expressing the G636C-FGFR4 mutant were significantly more sensitive to ASP5878, a selective FGFR inhibitor, than the control. Oral administration of ASP5878 significantly inhibited the growth of tumours in mice engrafted with G636C-FGFR4/3T3 cells. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncoprotein. These findings support the therapeutic targeting of FGFR4 in gastric cancer.


Subject(s)
Carcinogenesis/genetics , Proto-Oncogene Proteins/genetics , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Receptor, Fibroblast Growth Factor, Type 4/genetics , Stomach Neoplasms/genetics , 3T3 Cells , Animals , Carcinogenesis/drug effects , Humans , Male , Mice , Mutation , Phosphorylation/drug effects , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Receptor, Fibroblast Growth Factor, Type 4/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 4/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Signal Transduction/drug effects , Stomach/pathology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Xenograft Model Antitumor Assays
3.
J Neurochem ; 105(4): 1550-9, 2008 May.
Article in English | MEDLINE | ID: mdl-18248603

ABSTRACT

While the brain does not utilize fatty acids as a primary energy source, recent evidence shows that intermediates of fatty acid metabolism serve as hypothalamic sensors of energy status. Increased hypothalamic malonyl-CoA, an intermediate in fatty acid synthesis, is indicative of energy surplus and leads to the suppression of food intake and increased energy expenditure. Malonyl-CoA functions as an inhibitor of carnitine palmitoyl-transferase 1 (CPT1), a mitochondrial outer membrane enzyme that initiates translocation of fatty acids into mitochondria for oxidation. The mammalian brain expresses a unique homologous CPT1, CPT1c, that binds malonyl-CoA tightly but does not support fatty acid oxidation in vivo, in hypothalamic explants or in heterologous cell culture systems. CPT1c knockout (KO) mice under fasted or refed conditions do not exhibit an altered CNS transcriptome of genes known to be involved in fatty acid metabolism. CPT1c KO mice exhibit normal levels of metabolites and of hypothalamic malonyl-CoA and fatty acyl-CoA levels either in the fasted or refed states. However, CPT1c KO mice exhibit decreased food intake and lower body weight than wild-type littermates. In contrast, CPT1c KO mice gain excessive body weight and body fat when fed a high-fat diet while maintaining lower or equivalent food intake. Heterozygous mice display an intermediate phenotype. These findings provide further evidence that CPT1c plays a role in maintaining energy homeostasis, but not through altered fatty acid oxidation.


Subject(s)
Body Weight/physiology , Brain/metabolism , Carnitine O-Palmitoyltransferase/physiology , Eating/physiology , Fatty Acids/metabolism , Animals , Body Weight/genetics , Brain/enzymology , CHO Cells , COS Cells , Carnitine O-Palmitoyltransferase/genetics , Central Nervous System/enzymology , Central Nervous System/metabolism , Chlorocebus aethiops , Cricetinae , Cricetulus , Eating/genetics , Fatty Acids/genetics , Female , Isoenzymes/genetics , Isoenzymes/physiology , Lipid Metabolism/genetics , Lipid Metabolism/physiology , Male , Mice , Mice, Knockout , Oxidation-Reduction
4.
Proc Natl Acad Sci U S A ; 103(19): 7282-7, 2006 May 09.
Article in English | MEDLINE | ID: mdl-16651524

ABSTRACT

Fatty acid synthesis in the central nervous system is implicated in the control of food intake and energy expenditure. An intermediate in this pathway, malonyl-CoA, mediates these effects. Malonyl-CoA is an established inhibitor of carnitine palmitoyltransferase-1 (CPT1), an outer mitochondrial membrane enzyme that controls entry of fatty acids into mitochondria and, thereby, fatty acid oxidation. CPT1c, a brain-specific enzyme with high sequence similarity to CPT1a (liver) and CPT1b (muscle) was recently discovered. All three CPTs bind malonyl-CoA, and CPT1a and CPT1b catalyze acyl transfer from various fatty acyl-CoAs to carnitine, whereas CPT1c does not. These findings suggest that CPT1c has a unique function or activation mechanism. We produced a targeted mouse knockout (KO) of CPT1c to investigate its role in energy homeostasis. CPT1c KO mice have lower body weight and food intake, which is consistent with a role as an energy-sensing malonyl-CoA target. Paradoxically, CPT1c KO mice fed a high-fat diet are more susceptible to obesity, suggesting that CPT1c is protective against the effects of fat feeding. CPT1c KO mice also exhibit decreased rates of fatty acid oxidation, which may contribute to their increased susceptibility to diet-induced obesity. These findings indicate that CPT1c is necessary for the regulation of energy homeostasis.


Subject(s)
Brain/enzymology , Carnitine O-Palmitoyltransferase/metabolism , Homeostasis , Animals , Body Weight , Carnitine/metabolism , Carnitine Acyltransferases/metabolism , Carnitine O-Palmitoyltransferase/chemistry , Carnitine O-Palmitoyltransferase/deficiency , Carnitine O-Palmitoyltransferase/genetics , Catalysis , Fats , Fatty Acids/metabolism , Feeding Behavior , Malonyl Coenzyme A/metabolism , Mice , Mice, Knockout , Oxidation-Reduction , Protein Binding
5.
J Biochem ; 137(2): 147-55, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15749829

ABSTRACT

The processing of beta-amyloid precursor protein (APP) generates the amyloid beta-protein (A beta) and contributes to the development of Alzheimer's disease (AD). Elucidating the regulation of APP processing will, therefore, contribute to the understanding of AD. Many APP-binding proteins, such as FE65, X11s, and JNK-interacting proteins (JIPs), bind the motif 681-GYENPTY-687 within the cytoplasmic domain of APP. Here we found that the human homologue of yeast amino-terminal acetyltransferase ARD1 (hARD1) interacts with a novel motif, 658-HGVVEVD-664, in the cytoplasmic domain of APP695. hARD1 expressed its acetyltransferase activity in association with a human subunit homologous to another yeast amino-acetyltransferase, hNAT1. Co-expression of hARD1 and hNAT1 in cells suppressed A beta40 secretion and the suppression correlated with their enzyme activity. These observations suggest that the association of APP with hARD1 and hNAT1 and/or their N-acetyltransferase activity contributes to the regulation of A beta generation.


Subject(s)
Acetyltransferases/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Arylamine N-Acetyltransferase/metabolism , Acetyltransferases/analysis , Acetyltransferases/genetics , Amino Acid Motifs , Amino Acid Sequence , Amyloid beta-Protein Precursor/analysis , Amyloid beta-Protein Precursor/chemistry , Arylamine N-Acetyltransferase/genetics , Cells, Cultured , Cytoplasm/chemistry , Cytoplasm/metabolism , Humans , Isoenzymes , Molecular Sequence Data , Protein Structure, Tertiary , Two-Hybrid System Techniques
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