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1.
Biomed Pharmacother ; 175: 116670, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38692065

RESUMO

Neutrophils are heterogeneous and plastic, with the ability to polarize from antitumour to protumour phenotype and modulate tumour microenvironment components. While some advances have been made, the neutrophil-targeting therapy remains underexplored. Activation of formyl peptide receptors (FPRs) by formylated peptides is needed for local control of infection through the recruitment of activated neutrophils while the potential contribution of antitumour activity remains underexplored. Here, we demonstrate that neutrophils can be harnessed to suppress tumour growth through the action of the formyl peptide (FP) on the formyl peptide receptor (FPR). Mechanistically, FP efficiently recruits neutrophils to produce reactive oxygen species production (ROS), resulting in the direct killing of tumours. Antitumour functions disappeared when neutrophils were depleted by anti-Ly6G antibodies. Interestingly, extensive T-cell activation was observed in mouse tumours treated with FP, showing the potential to alter the immune suppressed tumour microenvironment (TME) and further sensitize mice to anti-PD1 therapy. Transcriptomic and flow cytometry analyses revealed the mechanisms of FP-sensitized anti-PD1 therapy, mainly including stimulated neutrophils and an altered immune-suppressed tumour microenvironment. Collectively, these data establish FP as an effective combination partner for sensitizing anti-PD1 therapy by stimulating tumour-infiltrated neutrophils.


Assuntos
Imunoterapia , Camundongos Endogâmicos C57BL , Neutrófilos , Receptores de Formil Peptídeo , Linfócitos T , Microambiente Tumoral , Animais , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Camundongos , Imunoterapia/métodos , Receptores de Formil Peptídeo/metabolismo , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Humanos , Feminino , Ativação de Neutrófilo/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ativação Linfocitária/efeitos dos fármacos , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia
2.
Cell Oncol (Dordr) ; 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38393513

RESUMO

PURPOSE: Sunitinib is a recommended drug for metastatic renal cell carcinoma (RCC). However, the therapeutic potential of sunitinib is impaired by toxicity and resistance. Therefore, we seek to explore a combinatorial strategy to improve sunitinib efficacy of low-toxicity dose for better clinical application. METHODS: We screen synergistic reagents of sunitinib from a compound library containing 1374 FDA-approved drugs by in vitro cell viability evaluation. The synergistically antiproliferative and proapoptotic effects were demonstrated on in vitro and in vivo models. The molecular mechanism was investigated by phosphoproteomics, co-immunoprecipitation, immunofluorescence and western-blot assays, etc. RESULTS: From the four-step screening, nilotinib stood out as a potential synergistic killer combined with sunitinib. Subsequent functional evaluation demonstrated that nilotinib and sunitinib synergistically inhibit RCC cell proliferation and promote apoptosis in vitro and in vivo. Mechanistically, nilotinib activates E3-ligase HUWE1 and in combination with sunitinib renders MCL-1 for degradation via proteasome pathway, resulting in the release of Beclin-1 from MCL-1/Beclin-1 complex. Subsequently, Beclin-1 induces complete autophagy flux to promote antitumor effect. CONCLUSION: Our findings revealed that a novel mechanism that nilotinib in combination with sunitinib overcomes sunitinib resistance in RCC. Therefore, this novel rational combination regimen provides a promising therapeutic avenue for metastatic RCC and rationale for evaluating this combination clinically.

3.
Acta Pharm Sin B ; 14(1): 223-240, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38261805

RESUMO

Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.

4.
Gastroenterology ; 166(3): 466-482, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38065340

RESUMO

BACKGROUND & AIMS: Although immunotherapy shows substantial advancement in colorectal cancer (CRC) with microsatellite instability high, it has limited efficacy for CRC with microsatellite stability (MSS). Identifying combinations that reverse immune suppression and prime MSS tumors for current immunotherapy approaches remains an urgent need. METHODS: An in vitro CRISPR screen was performed using coculture models of primary tumor cells and autologous immune cells from MSS CRC patients to identify epigenetic targets that could enhance immunotherapy efficacy in MSS tumors. RESULTS: We revealed EHMT2, a histone methyltransferase, as a potential target for MSS CRC. EHMT2 inhibition transformed the immunosuppressive microenvironment of MSS tumors into an immunomodulatory one by altering cytokine expression, leading to T-cell-mediated cytotoxicity activation and improved responsiveness to anti-PD1 treatment. We observed galectin-7 up-regulation upon EHMT2 inhibition, which converted a "cold" MSS tumor environment into a T-cell-inflamed one. Mechanistically, CHD4 repressed galectin-7 expression by recruiting EHMT2 to form a cotranscriptional silencing complex. Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, serving as a potent adjunct cytokine therapy. CONCLUSIONS: Our findings suggest that targeting the EHMT2/galectin-7 axis could provide a novel combination strategy for immunotherapy in MSS CRC.


Assuntos
Neoplasias Colorretais , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Imunoterapia , Citocinas , Galectinas/genética , Repetições de Microssatélites , Instabilidade de Microssatélites , Microambiente Tumoral , Antígenos de Histocompatibilidade , Histona-Lisina N-Metiltransferase
5.
Nat Commun ; 14(1): 6132, 2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37783727

RESUMO

Cyclic GMP-AMP synthase (cGAS) is an essential sensor of aberrant cytosolic DNA for initiating innate immunity upon invading pathogens and cellular stress, which is considered as a potential drug target for autoimmune and autoinflammatory diseases. Here, we report the discovery of a class of cyclopeptide inhibitors of cGAS identified by an in vitro screening assay from a focused library of cyclic peptides. These cyclopeptides specifically bind to the DNA binding site of cGAS and block the binding of dsDNA with cGAS, subsequently inhibit dsDNA-induced liquid phase condensation and activation of cGAS. The specificity and potency of one optimal lead XQ2B were characterized in cellular assays. Concordantly, XQ2B inhibited herpes simplex virus-1 (HSV-1)-induced antiviral immune responses and enhanced HSV-1 infection in vitro and in vivo. Furthermore, XQ2B significantly suppressed the elevated levels of type I interferon and proinflammatory cytokines in primary macrophages from Trex1-/- mice and systemic inflammation in Trex1-/- mice. XQ2B represents the specific cGAS inhibitor targeting protein-DNA interaction and phase separation and serves as a scaffold for the development of therapies in the treatment of cGAS-dependent inflammatory diseases.


Assuntos
DNA , Peptídeos Cíclicos , Animais , Camundongos , Peptídeos Cíclicos/farmacologia , DNA/metabolismo , Nucleotidiltransferases/metabolismo , Imunidade Inata , Citocinas
6.
Acta Pharm Sin B ; 13(8): 3382-3399, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37655321

RESUMO

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

7.
Chemistry ; 29(51): e202300655, 2023 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-37227809

RESUMO

Bioluminogenic probes emerged as powerful tools for imaging and analysis of various bioanalyses, but traditional approaches would be limited to the low sensitivity during determine the low activity of protease in clinical specimens. Herein, we proposed a caged luciferase inhibitor-based bioluminescence-switching strategy (CLIBS) by using a cleavable luciferase inhibitor to modulate the activity of luciferase reporter to amplify the detective signals, which led to the enhancement of detection sensitivity, and enabled the determination of circulating Aminopeptidase N (APN) activity in thousands of times diluted serum. By applying the CLIBS to serum samples in non-small cell lung cancer (NSCLC) patients from two clinical cohorts, we revealed that, for the first time, higher circulating APN activities but not its concentration, were associated with more NSCLC metastasis or higher metastasis stages by subsequent clinical analysis, and can serve as an independent factor for forecasting NSCLC patients' risk of metastasis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Antígenos CD13 , Luciferases
8.
Biochem Pharmacol ; 211: 115498, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36913990

RESUMO

Despite the use of targeted therapy in non-small cell lung cancer (NSCLC) patients, cisplatin (DDP)-based chemotherapy is still the main option. However, DDP resistance is the major factor contributing to the failure of chemotherapy. In this study, we tried to screen DDP sensitizers from an FDA-approved drug library containing 1374 small-molecule drugs to overcome DDP resistance in NSCLC. As a result, disulfiram (DSF) was identified as a DDP sensitizer: DSF and DDP had synergistic anti-NSCLC effects, which are mainly reflected in inhibiting tumor cell proliferation, plate colony formation and 3D spheroidogenesis and inducing apoptosis in vitro, as well as the growth of NSCLC xenografts in mice. Although DSF has recently been reported to promote the antitumor effect of DDP by inhibiting ALDH activity or modulating some important factors or pathways, unexpectedly, we found that DSF reacted with DDP to form a new platinum chelate, Pt(DDTC)3+, which might be one of the important mechanisms for their synergistic effect. Moreover, Pt(DDTC)3+ has a stronger anti-NSCLC effect than DDP, and its antitumor activity is broad-spectrum. These findings reveal a novel mechanism underlying the synergistic antitumor effect of DDP and DSF, and provide a drug candidate or a lead compound for the development of a new antitumor drug.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Camundongos , Animais , Cisplatino/farmacologia , Cisplatino/metabolismo , Dissulfiram/farmacologia , Platina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacologia , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral
9.
Mol Ther ; 31(2): 517-534, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36307991

RESUMO

N6-methyladenosine (m6A) is the most pervasive RNA modification and is recognized as a novel epigenetic regulation in RNA metabolism. Although the m6A modification involves various physiological processes, its roles in drug resistance in colorectal cancer (CRC) still remain unknown. We analyzed the RNA expression profile of m6A/A (%) with MRM mass spectrometry in human 5-fluorouracil (5-FU)-resistant CRC tissues, and used the m6A RNA immunoprecipitation assay to validate the m6A-regulated target. Our results have shown that the m6A demethylase FTO was up-regulated in human primary and 5-FU-resistant CRC. Depletion of FTO decreased cell growth, colony formation and metastasis in 5-FU-resistant CRC cells in vitro and in vivo. Mechanistically, we identified SIVA1, a critical apoptotic gene, as a key downstream target of the FTO-mediated m6A demethylation. The m6A demethylation of SIVA1 at the CDS region induced its mRNA degradation via a YTHDF2-dependent mechanism. The SIVA1 levels were negatively correlated with the FTO levels in clinical CRC tissues. Notably, inhibition of FTO significantly reduced the tolerance of 5-FU in 5-FU-resistant CRC cells via the FTO-SIVA1 axis, whereas SIVA1-depletion could restore the m6A-dependent 5-FU sensitivity in CRC cells. In summary, our findings demonstrate a critical role of FTO as an m6A demethylase enhancing chemo-resistance in CRC cells, and suggest that FTO inhibition may restore the sensitivity of chemo-resistant CRC cells to 5-FU.


Assuntos
Neoplasias Colorretais , Epigênese Genética , Humanos , RNA , Fluoruracila/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo
10.
Cell Oncol (Dordr) ; 45(6): 1347-1361, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36205846

RESUMO

PURPOSE: The adaptive immune responses induced by radiotherapy has been demonstrated to largely rely on STING-dependent type I interferons (IFNs) production. However, irradiated tumor cells often fail to induce dendritic cells (DCs) to produce type I IFNs. Hence, we aim to uncover the limitation of STING-mediated innate immune sensing following radiation, and identify efficient reagents capable to rescue the failure of type I IFNs induction for facilitating radiotherapy. METHODS: A targeted cell-based phenotypic screening was performed to search for active molecules that could elevate the production of type I IFNs. USP14 knockout or inhibition was assayed for IFN production and the activation of STING signaling in vitro. The mechanisms of USP14 were investigated by western blot and co-immunoprecipitation in vitro. Additionally, combinational treatments with PT33 and radiation in vivo and in vitro models were performed to evaluate type I IFNs responses to radiation. RESULTS: PT33 was identified as an enhancer of STING agonist elicited type I IFNs production to generate an elevated and durable STING activation profile in vitro. Mechanistically, USP14 inhibition or deletion impairs the deubiquitylation of K63-linked IRF3. Furthermore, blockade of USP14 with PT33 enhances DC sensing of irradiated-tumor cells in vitro, and synergizes with radiation to promote systemic antitumor immunity in vivo. CONCLUSION: Our findings reveal that USP14 is one of the major IFN production suppressors and impairs the activation of IRF3 by removing the K63-linked ubiquitination of IRF3. Therefore, blockage of USP14 results in the gain of STING signaling activation and radiation-induced adaptive immune responses.


Assuntos
Imunidade Adaptativa , Interferon Tipo I , Interferon beta , Radioterapia , Ubiquitina Tiolesterase , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon , Interferon Tipo I/metabolismo , Interferon beta/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
11.
Mol Ther Oncolytics ; 26: 330-346, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36090478

RESUMO

The use of radiotherapy for hypopharyngeal cancer (HC) treatment is increasing, and it is currently the primary treatment option for this cancer. However, radioresistance occurs in a proportion of patients. Here, we found that radiation increased proteasomal gene expression and that proteasome assembly was dependent on the induction of transcription factor NRF1 in HC. Through screening assays, we identified a mechanism by which proteasome-mediated degradation of DEP domain-containing mTOR-interacting protein (DEPTOR) contributes to the elevation of mTORC1 signaling after radiation. Therefore, after treatment with proteasome inhibitors (PIs), stabilization of DEPTOR inhibited mTORC1 signaling elevated by radiation and ultimately sensitized HC to radiotherapy. Mechanically, PIs not only interrupted the deubiquitination and degradation of DEPTOR but also suppressed the ubiquitination of DEPTOR mediated by ß-TrCP. Clinically, the high levels of DEPTOR in HC cells were associated with sensitivity to radiotherapy and favorable prognosis. Stabilizing DEPTOR through targeting proteasome-mediated degradation is a potential strategy for sensitizing HC to radiotherapy.

12.
Antioxid Redox Signal ; 37(16-18): 1266-1290, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35369726

RESUMO

Significance: Immunotherapy, which utilizes the patient's immune system to fight tumor cells, has been approved for the treatment of some types of advanced cancer. Recent Advances: The complexity and diversity of tumor immunity are responsible for the varying response rates toward current immunotherapy strategies and highlight the importance of exploring regulators in tumor immunotherapy. Several genetic factors have proved to be critical regulators of tumor immunotherapy. RNAs, including messenger RNAs and non-coding RNAs, play vital and diverse roles in tumorigenesis, metastasis, drug resistance, and immunotherapy response. RNA modifications, including N6-methyladenosine methylation, are involved in tumor immunity. Critical Issues: A critical issue is the lack of summary of the regulatory RNA molecules and their derivatives in mediating immune activities in human cancers that could provide potential applications for tumor immunotherapeutic strategy. Future Directions: This review summarizes the dual roles (the light and dark sides) of RNA and its derivatives in tumor immunotherapy and discusses the development of RNA-based therapies as novel immunotherapeutic strategies for cancer treatment. Antioxid. Redox Signal. 37, 1266-1290.


Assuntos
Adenosina , RNA , Humanos , RNA/genética , RNA Mensageiro , Carcinogênese , Transformação Celular Neoplásica
13.
ACS Med Chem Lett ; 13(2): 304-311, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35178187

RESUMO

The extensive applications of Firefly luciferase (Fluc) in numerous biological, biomedical, and clinical investigations rendered an urgent need for efficient and biocompatible Fluc inhibitors for the construction of novel assay platforms. Herein we describe the identification of 2-benzylidene-tetralone derivatives as highly potent and reversible Firefly luciferase inhibitors by competing with d-luciferin. The most active compound 48 was found to have >7000 fold higher potency (IC50 = 0.25 nM) than that of the well-known luciferase inhibitor resveratrol (IC50 = 1.9 µM) biochemically with sub- to low nanomolar IC50 values, and it can efficiently block the Fluc generated bioluminescence in vivo.

14.
Hepatology ; 74(3): 1461-1479, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33813748

RESUMO

BACKGROUND AND AIMS: Hypoxia is a common feature of the tumor microenvironment (TME), which promotes tumor progression, metastasis, and therapeutic drug resistance through a myriad of cell activities in tumor and stroma cells. While targeting hypoxic TME is emerging as a promising strategy for treating solid tumors, preclinical development of this approach is lacking in the study of HCC. APPROACH AND RESULTS: From a genome-wide CRISPR/CRISPR-associated 9 gene knockout screening, we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as an essential driver for HCC cell growth under hypoxia. Knockdown of ALDOA in HCC cells leads to lactate depletion and consequently inhibits tumor growth. Supplementation with lactate partly rescues the inhibitory effects mediated by ALDOA knockdown. Upon hypoxia, ALDOA is induced by hypoxia-inducible factor-1α and fat mass and obesity-associated protein-mediated N6 -methyladenosine modification through transcriptional and posttranscriptional regulation, respectively. Analysis of The Cancer Genome Atlas shows that elevated levels of ALDOA are significantly correlated with poor prognosis of patients with HCC. In a screen of Food and Drug Administration-approved drugs based on structured hierarchical virtual platforms, we identified the sulfamonomethoxine derivative compound 5 (cpd-5) as a potential inhibitor to target ALDOA, evidenced by the antitumor activity of cpd-5 in preclinical patient-derived xenograft models of HCC. CONCLUSIONS: Our work identifies ALDOA as an essential driver for HCC cell growth under hypoxia, and we demonstrate that inhibition of ALDOA in the hypoxic TME is a promising therapeutic strategy for treating HCC.


Assuntos
Carcinoma Hepatocelular/genética , Frutose-Bifosfato Aldolase/genética , Neoplasias Hepáticas/genética , Hipóxia Tumoral/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Frutose-Bifosfato Aldolase/metabolismo , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ácido Láctico/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Mutação com Perda de Função , Camundongos , Transplante de Neoplasias , Sulfamonometoxina/análogos & derivados , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Gut ; 70(9): 1698-1712, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33219048

RESUMO

OBJECTIVE: Dysregulated cellular metabolism is a distinct hallmark of human colorectal cancer (CRC). However, metabolic programme rewiring during tumour progression has yet to be fully understood. DESIGN: We analysed altered gene signatures during colorectal tumour progression, and used a complex of molecular and metabolic assays to study the regulation of metabolism in CRC cell lines, human patient-derived xenograft mouse models and tumour organoid models. RESULTS: We identified a novel RNA-binding protein, RALY (also known as hnRNPCL2), that is highly associated with colorectal tumour aggressiveness. RALY acts as a key regulatory component in the Drosha complex, and promotes the post-transcriptional processing of a specific subset of miRNAs (miR-483, miR-676 and miR-877). These miRNAs systematically downregulate the expression of the metabolism-associated genes (ATP5I, ATP5G1, ATP5G3 and CYC1) and thereby reprogramme mitochondrial metabolism in the cancer cell. Analysis of The Cancer Genome Atlas (TCGA) reveals that increased levels of RALY are associated with poor prognosis in the patients with CRC expressing low levels of mitochondrion-associated genes. Mechanistically, induced processing of these miRNAs is facilitated by their N6-methyladenosine switch under reactive oxygen species (ROS) stress. Inhibition of the m6A methylation abolishes the RALY recognition of the terminal loop of the pri-miRNAs. Knockdown of RALY inhibits colorectal tumour growth and progression in vivo and in organoid models. CONCLUSIONS: Collectively, our results reveal a critical metabolism-centric role of RALY in tumour progression, which may lead to cancer therapeutics targeting RALY for treating CRC.


Assuntos
Ribonucleoproteínas Nucleares Heterogêneas Grupo C/metabolismo , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Espécies Reativas de Oxigênio/metabolismo , Ribonuclease III/metabolismo
16.
J Med Chem ; 63(19): 11286-11301, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32844651

RESUMO

Blockade of immune checkpoint PD-1/PD-L1 facilitates the rescue of immune escapes of tumor cells. Though various monoclonal antibodies have been approved for clinical therapy, the development of small molecular inhibitors lags behind antibodies partially owing to the challenges of protein-protein interaction (PPI) blocker design. In this work, we adopted the skeleton of natural cyclopeptidic antibiotics gramicidin S as the start point for PD-1/PD-L1 inhibitor exploring and discovered a series of novel cyclopeptides that could interfere with the PPI of PD-1/PD-L1 based on several rounds of structural design and optimization. The representative active cyclopeptide 66 can bind two PD-L1 and efficiently block the PD-1/PD-L1 interaction, recruit the immune cells to the tumor cells, enhance their killing against tumor cells by promoting the release of granzyme B and perforin, and display significant CD8+ T cell-dependent tumor suppression activity in vivo.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Desenho de Fármacos , Imunoterapia , Neoplasias/tratamento farmacológico , Peptídeos Cíclicos/química , Humanos
18.
EMBO J ; 39(12): e103181, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32368828

RESUMO

N6-methyladenosine (m6 A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary m6 A methyltransferase, is significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy-associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m6 A modification of the FOXO3 mRNA 3'-untranslated region increasing its stability through a YTHDF1-dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3-mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m6 A-dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3-mediated m6 A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of m6 A modification in the resistance of HCC to sorafenib therapy.


Assuntos
Adenosina/análogos & derivados , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Mensageiro/metabolismo , RNA Neoplásico/metabolismo , Sorafenibe/farmacologia , Adenosina/genética , Adenosina/metabolismo , Animais , Autofagia/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proteína Forkhead Box O3/genética , Células HEK293 , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Metilação/efeitos dos fármacos , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/genética , RNA Mensageiro/genética , RNA Neoplásico/genética
19.
Chem Commun (Camb) ; 56(19): 2881-2884, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32037404

RESUMO

The first proteolysis targeting chimeras for the intracellular elimination of transforming growth factor-ß1 (TGF-ß1), which contributes to various diseases, are described. The appropriately designed DT-6 could efficiently degrade intracellular TGF-ß1, and inhibit M2 macrophage induced epithelial to mesenchymal transition and invasive migration of cancer cells.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Transição Epitelial-Mesenquimal , Células Hep G2 , Humanos , Invasividade Neoplásica
20.
J Biochem Mol Toxicol ; 33(11): e22395, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31583774

RESUMO

Raloxifene, a selective estrogen receptor modulator, displays benefits for Alzheimer's disease (AD) prevention in postmenopausal women as hormonal changes during menopause have the potential to influence AD pathogenesis, but the underlying mechanism of its neuroprotection is not entirely clear. In this study, the effects of raloxifene on amyloid-ß (Aß) amyloidogenesis were evaluated. The results demonstrated that raloxifene inhibits Aß42 aggregation and destabilizes preformed Aß42 fibrils through directly interacting with the N-terminus and middle domains of Aß42 peptides. Consequently, raloxifene not only reduces direct toxicity of Aß42 in HT22 neuronal cells, but also suppresses expressions of tumor necrosis factor-α and transforming growth factor-ß induced by Aß42 peptides, and then alleviates microglia-mediated indirect toxicity of Aß42 to HT22 neuronal cells. Our results suggested an alternative possible explanation for the neuroprotective activity of raloxifene in AD prevention.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Agregados Proteicos/efeitos dos fármacos , Cloridrato de Raloxifeno/farmacologia , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Microglia/citologia , Microglia/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/química , Agregação Patológica de Proteínas/metabolismo , Domínios Proteicos , Cloridrato de Raloxifeno/química , Fator de Crescimento Transformador beta/genética , Fator de Necrose Tumoral alfa/genética
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