RESUMO
The rotational spectrum of an acrolein-formaldehyde complex has been characterized using pulsed jet Fourier transform microwave spectroscopy complemented with quantum chemical calculations. One isomer has been observed in pulsed jets, which is stabilized by a dominant O=Câ¯O tetrel bond (n â π* interaction) and a secondary C-Hâ¯O hydrogen bond. Splittings arising from the internal rotation of formaldehyde around its C2v axis were also observed, from which its V2 barrier was evaluated. It seems that when V2 equals or exceeds 4.61 kJ mol-1, no splitting of the spectral lines of the rotational spectrum was observed. The nature of the non-covalent interactions of the target complex is elucidated through natural bond orbital analysis. These findings contribute to a deeper understanding on the non-covalent interactions within the dimeric complex formed by two aldehydes.
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A high level of PD-L1 in cancer cells promotes tumor immune escape and inhibits tumor immunotherapy. Although PD-L1 gene expression is upregulated by multiple pathways, its gene transcriptional repression is still unclear. Here we found that loss of PPARα, one of the peroxisome-proliferator-activated receptors (PPARs) family members, promoted colorectal tumor immune escape. Mechanistically, PPARα directly bound to the PD-L1 promoter resulting in its gene transcriptional repression, which in turn increased T cell activity, and PPARα agonist enhanced this event. However, ERK induced PPARα-S12 phosphorylation leading to blockade of PPARα-mediated PD-L1 transcriptional repression, and the combination of ERK inhibitor with PPARα agonist significantly inhibited tumor immune escape. These findings suggest that the ERK-PPARα pathway inhibited PD-L1 gene transcriptional repression and promoted colorectal tumor immune escape.
Assuntos
Antígeno B7-H1 , Neoplasias Colorretais , PPAR alfa , Evasão Tumoral , PPAR alfa/metabolismo , PPAR alfa/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Humanos , Fosforilação , Animais , Camundongos , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Sistema de Sinalização das MAP QuinasesRESUMO
Immune cells can protect against tumor progression by killing cancer cells, while aberrant expression of the immune checkpoint protein PD-L1 (programmed death ligand 1) in cancer cells facilitates tumor immune escape and inhibits anti-tumor immunotherapy. As a serine/threonine kinase, CK2 (casein kinase 2) regulates tumor progression by multiple pathways, while it is still unclear the effect of CK2 on tumor immune escape. Here it is found that ING4 induced PD-L1 autophagic degradation and inhibites non-small cell lung cancer (NSCLC) immune escape by increasing T cell activity. However, clinical analysis suggests that high expression of CK2 correlates with low ING4 protein level in NSCLC. Further analysis shows that CK2 induce ING4-S150 phosphorylation leading to ING4 ubiquitination and degradation by JFK ubiquitin ligase. In contrast, CK2 gene knockout increases ING4 protein stability and T cell activity, subsequently, inhibites NSCLC immune escape. Furthermore, the combined CK2 inhibitor with PD-1 antibody effectively enhances antitumor immunotherapy. These findings provide a novel strategy for cancer immunotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Antígeno B7-H1/metabolismo , Caseína Quinase II/uso terapêutico , Imunoterapia , Proteínas de Homeodomínio , Proteínas de Ciclo Celular , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/uso terapêuticoRESUMO
The rotational spectrum of acetoin (3-hydroxy-2-butanone) was measured by using Fourier transform microwave spectroscopy with the aid of quantum chemical calculations. Only one conformer of acetoin was detected in the pulsed jet, whose spectrum featured the splittings raised from the internal rotation of the methyl top linking to the CâO group. Based on the spectroscopic result, radio-astronomical searches for acetoin were carried out toward the massive star-forming region Sgr B2(N) using the Shanghai Tianma 65 m and IRAM 30 m radio telescopes. No lines belonging to acetoin were detected toward Sgr B2(N). Its upper limit of column density was calculated.
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Blockade of the programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) immune checkpoint could increase antitumor immunotherapy for multiple types of cancer, but the response rate of patients is about 10%-40%. Peroxisome proliferator activated receptor γ (PPARγ) plays an important role in regulating cell metabolism, inflammation, immunity, and cancer progression, while the mechanism of PPARγ on cancer cell immune escape is still unclear. Here we found that PPARγ expression exhibits a positive correlation with activation of T cells in non-small-cell lung cancer (NSCLC) by clinical analysis. Deficiency of PPARγ promoted immune escape of NSCLC by inhibiting T-cell activity, which was associated with increased PD-L1 protein level. Further analysis showed that PPARγ reduced PD-L1 expression independent of its transcriptional activity. PPARγ contains the microtubule-associated protein 1A/1B-light chain 3 (LC3) interacting region motif, which acts as an autophagy receptor for PPARγ binding to LC3, leading to degradation of PD-L1 in lysosomes, which in turn suppresses NSCLC tumor growth by increasing T-cell activity. These findings suggest that PPARγ inhibits the tumor immune escape of NSCLC by inducing PD-L1 autophagic degradation.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Antígeno B7-H1 , PPAR gama , Evasão TumoralRESUMO
Peroxisome proliferator-activated receptor δ (PPARδ) is a nuclear receptor transcription factor that plays an important role in the regulation of metabolism, inflammation, and cancer. In addition, the nutrient-sensing kinase 5'AMP-activated protein kinase (AMPK) is a critical regulator of cellular energy in coordination with PPARδ. However, the molecular mechanism of the AMPK/PPARδ pathway on cancer progression is still unclear. Here, we found that activated AMPK induced PPARδ-S50 phosphorylation in cancer cells, whereas the PPARδ/S50A (nonphosphorylation mimic) mutant reversed this event. Further analysis showed that the PPARδ/S50E (phosphorylation mimic) but not the PPARδ/S50A mutant increased PPARδ protein stability, which led to reduced p62/SQSTM1-mediated degradation of misfolded PPARδ. Furthermore, PPARδ-S50 phosphorylation decreased PPARδ transcription activity and alleviated PPARδ-mediated uptake of glucose and glutamine in cancer cells. Soft agar and xenograft tumor model analysis showed that the PPARδ/S50E mutant but not the PPARδ/S50A mutant inhibited colon cancer cell proliferation and tumor growth, which was associated with inhibition of Glut1 and SLC1A5 transporter protein expression. These findings reveal a new mechanism of AMPK-induced PPARδ-S50 phosphorylation, accumulation of misfolded PPARδ protein, and inhibition of PPARδ transcription activity contributing to the suppression of colon tumor formation.
Assuntos
Adenilato Quinase/metabolismo , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Glucose/metabolismo , Glutamina/metabolismo , PPAR gama/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Camundongos Nus , FosforilaçãoRESUMO
The rotational spectrum of the 1 : 1 benzaldehyde-formaldehyde complex has been investigated by pulsed jet Fourier transform microwave spectroscopy combined with ab initio calculations. The two most stable isomers were observed, with the relative abundance ratio NI/NII≈ 3/1 estimated with intensity measurements. Both observed isomers are stabilized by one dominating O[double bond, length as m-dash]CO tetrel bond (n âπ* interaction) and one secondary C-HO hydrogen bond. Natural bond orbital analysis and electron localization function analysis were applied to characterize the nature of the noncovalent interactions in the target complex.
RESUMO
The ability and preference of 3-oxetanone to form hydrogen or tetrel bonds have been investigated in its complexes with water and formaldehyde by using Fourier transform microwave spectroscopy complemented with quantum chemical calculations. Different types of interactions and internal dynamics have been observed in the targeted complexes. With water, the ether oxygen of 3-oxetanone is the favoured interaction site forming a classical O-HO hydrogen bond. Quite differently, the carbonyl group of 3-oxetanone plays the dual role as a tetrel donor and a proton acceptor in the 3-oxetanone-formaldehyde complex, featuring the CO tetrel bond and C-HO weak hydrogen bond interactions. Splittings originated from the internal rotation of formaldehyde around its C2 axis were also observed. The V2 barrier was estimated to be 375(10) cm-1 based on Meyer's one-dimensional flexible model. The changes in geometries and electronic densities upon complexation would shed light on the impact of archetype solvent and organic substrate molecules on the reactivity of 3-oxetanone.
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Epidermal growth factor receptor (EGFR) induces peroxisome-proliferator-activated receptor-δ (PPARδ)-Y108 phosphorylation, while it is unclear the effect of phosphorylation of PPARδ on cancer cell metabolism. Here we found that EGF treatment increased its protein stability by inhibiting its lysosomal dependent degradation, which was reduced by gefitinib (EGFR inhibitor) treatment. PPARδ-Y108 phosphorylation in response to EGF recruited HSP90 (heat shock protein 90) to PPARδ resulting in increased PPARδ stability. In addition, PPARδ-Y108 phosphorylation promoted cancer cell metabolism, proliferation, and chemoresistance. Therefore, this study revealed a novel molecular mechanism of EGFR/HSP90/PPARδ pathway-mediated cancer cell metabolism, proliferation, and chemoresistance, which provides a strategy for cancer treatment.
Assuntos
Receptores ErbB/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , PPAR delta/metabolismo , Western Blotting , Proliferação de Células/genética , Proliferação de Células/fisiologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Proteínas de Choque Térmico HSP90/genética , Células HT29 , Células HeLa , Humanos , Imunoprecipitação , PPAR delta/genética , Fosforilação/genética , Fosforilação/fisiologia , Estabilidade ProteicaRESUMO
Programmed death ligand 1 (PD-L1, CD274) is an essential immune checkpoint protein that binds to programmed death 1 (PD-1) on T-lymphocytes. T cell plays a critical role in killing cancer cells while the cancer cell exhibits immune escape by the expression of PD-L1. The binding of PD-L1 to PD-1 inhibits T cell proliferation and activity, leading to tumor immunosuppression. Increasing evidence shows that PD-L1 protein undergoes degradation in proteasomes or lysosomes by multiple pathways, leading to enhanced immunotherapy for cancer. Although some specific drugs induce PD-L1 degradation and increase antitumor activity, the combination of these drugs with PD-L1/PD-1 blockade significantly enhances cancer immunotherapy. In this review, we have discussed the interaction of PD-L1 degradation with cancer immunotherapy.
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Antígeno B7-H1/metabolismo , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Proteólise , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
In response to nutrient deficiency, autophagy degrades cytoplasmic materials and organelles in lysosomes, which is nutrient recycling, whereas activation of EGFR mediates autophagy suppression in response to growth factors. It is unclear whether PPARδ could be the regulator of autophagy in response to active EGFR. Here we found that EGFR induced PPARδ phosphorylation at tyrosine-108 leading to increased binding of LC3 to PPARδ by its LIR (LC3 interacting region) motif, consequently, inhibited autophagic flux. Conversely, EGFR inhibitor treatment reversed this event. Furthermore, EGFR-mediated PPARδ phosphorylation at tyrosine-108 led to autophagy inhibition and tumor growth. These findings suggest that PPARδ serves as a regulator of autophagy by its phosphorylation.
Assuntos
Autofagia/fisiologia , PPAR delta/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gefitinibe/farmacologia , Células HCT116 , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação , PPAR delta/genética , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Tirosina/genética , Tirosina/metabolismoRESUMO
As a nuclear receptor, peroxisome-proliferator-activated receptor α (PPARα) plays a critical role in regulation of metabolism and cancer, while the effect of PPARα agonist on cancer cell glucose metabolism-linked tumor growth is still unclear. Here we found that PPARα agonist (Wy14,643) decreased Glut1 (Glucose transporter 1) gene and protein expressions of colorectal cancer cell lines in response to normoxia or hypoxia. Dual-luciferase analysis showed that Wy14,643 inhibited Glut1 transcription activity. Importantly, ChIP-qPCR analysis showed that Wy14,643 increased the binding of PPARα to Glut1 promoter region. Wy14,643 suppressed Glut1 transcription activity resulting in reduced influx of glucose in cancer cells in response to normoxia or hypoxia. Further analysis showed that Wy14,643-mediated inhibition of tumor growth and chemo-resistance was associated with inhibition of mTOR pathway. Taken together, PPARα agonist Wy14,643 suppressed Glut1 transcription activity, glucose uptake and mTOR pathway in colorectal cancer cells, which was involved in reduced tumor growth and chemo-resistance. These findings provided a novel therapy strategy for cancer progression.
Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glucose/metabolismo , PPAR alfa/agonistas , Animais , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Humanos , Camundongos , Pirimidinas/farmacologia , Transcrição Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
As a nuclear receptor, ligand binding and activated PPARδ (peroxisome-proliferator-activated receptor δ) plays an important role in regulation of inflammation, metabolism and cancer, while it is unclear the effect of metformin on PPARδ-mediated cancer cell metabolism. Here we found that PPARδ agonist GW501516 significantly increased Glut1 (Glucose transporter 1) and SLC1A5 (solutecarrier family 1 member 5) gene and protein expressions in HCT-116, SW480, HeLa, and MCF-7 cancer cell lines, while metformin inhibited this event, which was associated with metformin-mediated inhibition of PPARδ activity in response to GW501516. Importantly, GW501516 inhibited the binding of PPARδ to AMPK, while metformin reversed this process. Metformin inhibited Glut1 and SLC1A5 expressions leading to reduced influx of glucose and glutamine in cancer cells, which is associated with reduced tumor growth. These findings suggest that metformin inhibited PPARδ agonist GW501516-induced cancer cell metabolism and tumor growth.
Assuntos
Sistema ASC de Transporte de Aminoácidos/genética , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/genética , Metformina/farmacologia , Antígenos de Histocompatibilidade Menor/genética , PPAR delta/agonistas , Tiazóis/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Glucose/metabolismo , Glutamina/metabolismo , Humanos , Camundongos , Tiazóis/farmacologia , Transcrição Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Two flavone di-C-glycosides, a pair of isomers, were isolated from Scutellaria baicalensis. The structures of compounds 1 and 2 were elucidated by means of physical data, including 1D and 2D NMR and HR-ESI-MS. Supporting theoretical calculations of the compound conformational landscape has also been conducted for geometry optimization. This is the first report of the natural occurrence of ß-furanoarabinoside. In addition, the effects of compounds 1 and 2 on NO, pro-inflammatory cytokines, PGE2 and COX-2 levels were measured in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. The pair of isomers exhibited significant inhibitory effects on inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Flavonas/isolamento & purificação , Scutellaria baicalensis/química , Animais , Dinoprostona/biossíntese , Flavonas/química , Flavonas/farmacologia , Interleucina-6/biossíntese , Lipopolissacarídeos/farmacologia , Camundongos , Células RAW 264.7RESUMO
The 1, 2, 3, 4-tetrafluorobenzene-water complex was investigated by pulsed-jet Fourier transform microwave spectroscopy. One isomer was detected in the jet expansion. Ab initio calculations and non-covalent interaction (NCI) analysis were performed to characterize the intermolecular NCIs. In the observed isomer, the water molecule lies almost in the plane of the benzene ring acting as a proton donor to one of the fluorine atoms and as an acceptor to one of the hydrogen atoms forming a six-membered ring structure. The CHâ¯O and Hâ¯FC bonding distances are determined to be 2.385(1) Å and 2.429(1) Å, respectively. The interaction energy is calculated to be -18.0 kJ mol-1 at the SAPT2+(3)/aug-cc-pVDZ level of theory. The observed transitions exhibit splitting in the order of tens to hundreds of kHz due to the internal rotation of water moiety. The possible tunneling paths of water were investigated by ab initio calculations resulting in a barrier for an internal rotation of about 201 cm-1.
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The rotational spectra of two isotopologues have been recorded and interpreted for the van der Waals complex chlorotrifluoroethylene-argon, by using pulsed jet Fourier transform microwave technique. Argon locates out of the ethylene plane, in the FCCF cavity of chlorotrifluoroethylene. The preference of the CFCl side over CF2 can be attributed to the presence of "π-hole" over the double bond in chlorotrifluoroethylene. Non-covalent interaction analysis indicated that the van der Waals interaction occurs between argon and two sites of chlorotrifluoroethylene (the π-system and the F atom of the CFCl top). The steric effect between Ar and the C-Cl bond repulses the Ar atom toward the C-F side.
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Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors including PPARα, PPARδ and PPARγ, which play an important role in regulating cancer cell proliferation, survival, apoptosis, and tumor growth. Activation of PPARs by endogenous or synthetic compounds regulates tumor progression in various tissues. Although each PPAR isotype suppresses or promotes tumor development depending on the specific tissues or ligands, the mechanism is still unclear. In this review, we summarized the regulative mechanism of PPARs on cancer progression.
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The molecular complex between iso-propanol and water has been investigated by Fourier transform microwave spectroscopy. Two distinct rotational spectra have been assigned, corresponding to two different isomers of the adduct. In both cases the water molecule acts as a proton donor to the alcoholic oxygen atom of iso-propanol in its gauche arrangement. The isomer in which the water molecule is oriented along the symmetry plane of the iso-propanol molecule (inner) is more stable than the second isomer, where the water is positioned outside the iso-propanol symmetry plane (outer). The rotational transitions of the inner isomer display a doubling, due to the two equivalent minima related to the internal rotation of the hydroxyl group (concerted with a rearrangement of the water unit). The tunneling splitting has been determined to be 25.16(8) GHz, corresponding to a B2 barrier of â¼440 cm-1.
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The rotational spectra of two isotopologues of chlorotrifluoroethylene-dimethyl ether show that the two constituent molecules are held together by a lone pair···π interaction. The ether oxygen is linked to the (CF2) carbon atom, with a C-O distance of 2.908 Å.
RESUMO
The rotational spectra of two isotopologues of the 1:1 complex between chlorotrifluoromethane and formaldehyde have been recorded and analyzed by using Fourier-transform microwave spectroscopy. Only one rotamer was detected, with the two constituent molecules held together through a Clâ â â O halogen bond (R(Clâ â â O) = 3.048â Å). The dimer displays two simultaneous large-amplitude intramolecular motions. The internal rotation of formaldehyde around its symmetry axis (V2 = 28(5)â cm(-1)) splits all the rotational transitions into two component lines with a relative intensity ratio of 1:3. On the other hand, the almost free internal rotation (V3 ≈ 2.5â cm(-1)) of the CF3 symmetric top increases the "rigid" value of the rotational constant A by almost one order of magnitude. In addition, all the transitions display a hyperfine structure due to the (35)Cl (or (37)Cl) nucleus quadrupole effects.