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1.
Exp Mol Med ; 56(5): 1123-1136, 2024 May.
Article in English | MEDLINE | ID: mdl-38689086

ABSTRACT

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC.


Subject(s)
Aspartic Acid , Carcinoma, Hepatocellular , Eukaryotic Translation Initiation Factor 5A , Glutamine , Hypoxia-Inducible Factor 1, alpha Subunit , Liver Neoplasms , Peptide Initiation Factors , RNA-Binding Proteins , Tumor-Associated Macrophages , Peptide Initiation Factors/metabolism , Peptide Initiation Factors/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Humans , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Tumor-Associated Macrophages/metabolism , Tumor-Associated Macrophages/immunology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Glutamine/metabolism , Aspartic Acid/metabolism , Aspartic Acid/analogs & derivatives , Protein Biosynthesis , Animals , Cell Line, Tumor , Mice , Glycolysis , Lysine/analogs & derivatives
2.
Mol Cell ; 80(4): 592-606.e8, 2020 11 19.
Article in English | MEDLINE | ID: mdl-33159855

ABSTRACT

Despite its outstanding clinical success, immune checkpoint blockade remains ineffective in many patients. Accordingly, combination therapy capable of achieving greater antitumor immunity is urgently required. Here, we report that limiting glutamine metabolism in cancer cells bolsters the effectiveness of anti-programmed death ligand-1 (PD-L1) antibody. Inhibition of glutamine utilization increased PD-L1 levels in cancer cells, thereby inactivating co-cultured T cells. Under glutamine-limited conditions, reduced cellular GSH levels caused an upregulation of PD-L1 expression by impairing SERCA activity, which activates the calcium/NF-κB signaling cascade. Consequently, in tumors grown in immunocompetent mice, inhibition of glutamine metabolism decreased the antitumor activity of T cells. In combination with anti-PD-L1, however, glutamine depletion strongly promoted the antitumor efficacy of T cells in vitro and in vivo due to simultaneous increases in Fas/CD95 levels. Our results demonstrate the relevance of cancer glutamine metabolism to antitumor immunity and suggest that co-targeting of glutamine metabolism and PD-L1 represents a promising therapeutic approach.


Subject(s)
Antibodies, Monoclonal/pharmacology , B7-H1 Antigen/metabolism , Glutamine/metabolism , Glutathione/metabolism , Neoplasms/immunology , Neoplasms/prevention & control , T-Lymphocytes/immunology , Aged , Animals , Apoptosis , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , Cell Proliferation , Female , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Neoplasms/metabolism , Neoplasms/pathology , Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
3.
Exp Ther Med ; 19(6): 3454-3460, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32373191

ABSTRACT

Excessive vascular smooth muscle cell (VSMC) proliferation contributes to the development of atherosclerosis and restenosis. Furthermore, apoptosis of VSMCs accelerates plaque rupture in the atherosclerotic vessels. Therefore, a strategy that regulates both VSMC proliferation and apoptosis is essential for the development of novel pharmacological tools for the treatment of atherosclerosis. Despite mounting evidence supporting the benefits of melatonin in diverse metabolic diseases, the role of melatonin in VSMC growth remains largely unknown. The present study revealed that melatonin inhibited both proliferation and apoptosis of primary cultured rat VSMCs. Melatonin induced mitochondrial energetic stress in VSMCs and subsequent induction of Sestrin2 via C/EBPß. Melatonin-induced Sestrin2 suppressed mTORC1 activity in VSMCs, contributing to suppression of VSMC proliferation. Additionally, melatonin-induced upregulation of Sestrin2 blocked apoptosis by preventing excessive ROS generation. The results demonstrated that melatonin controlled VSMC proliferation and apoptosis via Sestrin2-mediated inhibition of mTORC1 and ROS scavenging. Therefore, melatonin should be considered as a lead compound for therapies aimed at preventing vessel lumen constriction during the course of atherosclerosis and restenosis.

4.
EMBO Rep ; 20(6)2019 06.
Article in English | MEDLINE | ID: mdl-30988000

ABSTRACT

Oncogenic signals contribute to enhanced glycolysis and mTORC1 activity, leading to rapid cell proliferation in cancer. Regulation of glycolysis and mTORC1 by PI3K/Akt signaling is well established, but how KRAS-induced MEK signaling regulates these pathways remains poorly understood. Here, we report a role for MEK-driven lactate production in mTORC1 activation in KRAS-activated cells. KRAS/MEK-induced upregulation of the chicken ovalbumin upstream promoter transcriptional factor II (COUP-TFII) increases the expression of lactate dehydrogenase A (LDHA), resulting in lactate production and mTORC1 activation. Further, lactate inhibits the interaction of TSC2 and Rheb, leading to the cellular activation of mTORC1 irrespective of growth factor stimulation. These findings suggest that COUP-TFII is a novel oncogenic mediator, connecting KRAS signaling and glycolysis, and leading to mTORC1 activation and cellular growth.


Subject(s)
COUP Transcription Factor II/metabolism , Lactic Acid/biosynthesis , Mechanistic Target of Rapamycin Complex 1/metabolism , Proto-Oncogene Proteins p21(ras)/metabolism , Signal Transduction , COUP Transcription Factor II/genetics , Cell Line, Tumor , Gene Expression , Gene Knockdown Techniques , Glycolysis , Humans , Models, Biological , Ras Homolog Enriched in Brain Protein/metabolism , Tuberous Sclerosis Complex 2 Protein/metabolism
5.
Diabetes Metab J ; 43(6): 830-839, 2019 12.
Article in English | MEDLINE | ID: mdl-30877711

ABSTRACT

BACKGROUND: The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis. METHODS: We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and in vitro in human kidney tubular epithelial human renal proximal tubule cells (HK-2) cells, we further analyzed the effect of gemigliptin on transforming growth factor-ß (TGF-ß)-stimulated production of profibrotic proteins. RESULTS: Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1ß, which had all been markedly increased by UUO. In line with the in vivo results, TGF-ß markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin treatment. Furthermore, gemigliptin treatment attenuated phosphorylated nuclear factor-κB levels, which had been increased in the UUO kidney as well as in TGF-ß-treated cultured renal cells. CONCLUSION: The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.


Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Down-Regulation/drug effects , Inflammasomes/metabolism , Kidney Tubules, Proximal/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Piperidones/pharmacology , Protective Agents/pharmacology , Pyrimidines/pharmacology , Administration, Oral , Animals , Cell Line , Diabetic Nephropathies/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Fibrosis , Humans , Inflammation/metabolism , Mice , Mice, Inbred C57BL , Piperidones/administration & dosage , Piperidones/therapeutic use , Protective Agents/administration & dosage , Protective Agents/therapeutic use , Pyrimidines/administration & dosage , Pyrimidines/therapeutic use , Signal Transduction/drug effects , Transforming Growth Factor beta/metabolism , Ureteral Obstruction/complications , Ureteral Obstruction/metabolism
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