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1.
Cell Commun Signal ; 22(1): 335, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890746

RESUMO

OBJECTIVE: Kappa opioid receptor (KOR) signaling is involved in joint development and inflammation in Osteoarthritis (OA), while the biochemical mechanism remains unclarified. This study aims to investigate downstream molecular events of KOR activation, to provide novel perspectives in OA pathology. METHODS: U50,488H, a selective KOR agonist, was intra-articularly injected in mice upon destabilization of the medial meniscus (DMM) as OA models, with PBS injection as control. The behavioral and histological evaluation was assessed by hot plate test and red solid green staining, respectively. Alterations in mRNA and protein expression were assessed by RNA-seq, RT-qPCR, immunohistochemistry and western blotting (WB) in chondrocytes treated with TNF-α or TNF-α + U50,488H. Proteins interacted with KOR were explored using proximity labeling followed by mass spectrometry and then testified by co-immunoprecipitation (Co-IP) assay and immunofluorescence (IF). RESULTS: OA-induced pain was reduced and cartilage degeneration was alleviated upon KOR activation in DMM mice. In chondrocytes, activation of KOR reversed the upregulation of MMPs, IL-6, IL-1ß and phosphorylated(p-) STAT3, stimulated by TNF-α, while the expression of NF-κB, MAPKs and AKT signaling weren't reversed. RNA-seq and IF results presented that KOR activation evidently reduced STAT3 nuclear translocation in chondrocytes upon TNF-α stimuli. The reduction may be resulted from the binding of KOR and STAT3 in the plasma membrane, revealed by proximity labeling and Co-IP results. CONCLUSIONS: KOR activation protects cartilage from OA, and this protective effect is mainly exerted via sequestering STAT3 on the plasma membrane, resulting in inactivation of STAT3-dependent immune responses which otherwise contributes to OA.


Assuntos
Membrana Celular , Condrócitos , Osteoartrite , Receptores Opioides kappa , Fator de Transcrição STAT3 , Animais , Masculino , Camundongos , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Condrócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Osteoartrite/patologia , Osteoartrite/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides kappa/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo
2.
Cancer Biol Med ; 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38940675

RESUMO

Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. This cancer is determined by multiple (epi)genetic and environmental factors; can occur at distinct anatomic positions of the stomach; and displays high heterogeneity, with different cellular origins and diverse histological and molecular features. This heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient therapeutics. In the past decade, great progress has been made in the study of GC, particularly in molecular subtyping, investigation of the immune microenvironment, and defining the evolutionary path and dynamics. Preclinical mouse models, particularly immunocompetent models that mimic the cellular and molecular features of human GC, in combination with organoid culture and clinical studies, have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion, and the development of novel therapeutic strategies. Herein, we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models, emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.

3.
J Biol Chem ; 300(6): 107311, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38657866

RESUMO

The Hippo signaling pathway plays an essential role in organ size control and tumorigenesis. Loss of Hippo signal and hyper-activation of the downstream oncogenic YAP signaling are commonly observed in various types of cancers. We previously identified STRN3-containing PP2A phosphatase as a negative regulator of MST1/2 kinases (i.e., Hippo) in gastric cancer (GC), opening the possibility of selectively targeting the PP2Aa-STRN3-MST1/2 axis to recover Hippo signaling against cancer. Here, we further discovered 1) disulfiram (DSF), an FDA-approved drug, which can similarly block the binding of STRN3 to PP2A core enzyme and 2) CX-6258 (CX), a chemical inhibitor, that can disrupt the interaction between STRN3 and MST1/2, both allowing reactivation of Hippo activity to inhibit GC. More importantly, we found these two compounds, via an MST1/2 kinase-dependent manner, inhibit DNA repair to sensitize GC towards chemotherapy. In addition, we identified thiram, a structural analog of DSF, can function similarly to inhibit cancer cell proliferation or enhance chemotherapy sensitivity. Interestingly, inclusion of copper ion enhanced such effects of DSF and thiram on GC treatment. Overall, this work demonstrated that pharmacological targeting of the PP2Aa-STRN3-MST1/2 axis by drug compounds can potently recover Hippo signal for tumor treatment.


Assuntos
Dissulfiram , Via de Sinalização Hippo , Proteínas Serina-Treonina Quinases , Neoplasias Gástricas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Dissulfiram/farmacologia , Linhagem Celular Tumoral , Animais , Antineoplásicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Camundongos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator de Crescimento de Hepatócito/metabolismo , Proteína Fosfatase 2/metabolismo , Proteína Fosfatase 2/genética
4.
J Clin Invest ; 134(10)2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38512451

RESUMO

Lactylation has been recently identified as a new type of posttranslational modification occurring widely on lysine residues of both histone and nonhistone proteins. The acetyltransferase p300 is thought to mediate protein lactylation, yet the cellular concentration of the proposed lactyl-donor, lactyl-coenzyme A, is about 1,000 times lower than that of acetyl-CoA, raising the question of whether p300 is a genuine lactyltransferase. Here, we report that alanyl-tRNA synthetase 1 (AARS1) moonlights as a bona fide lactyltransferase that directly uses lactate and ATP to catalyze protein lactylation. Among the candidate substrates, we focused on the Hippo pathway, which has a well-established role in tumorigenesis. Specifically, AARS1 was found to sense intracellular lactate and translocate into the nucleus to lactylate and activate the YAP-TEAD complex; and AARS1 itself was identified as a Hippo target gene that forms a positive-feedback loop with YAP-TEAD to promote gastric cancer (GC) cell proliferation. Consistently, the expression of AARS1 was found to be upregulated in GC, and elevated AARS1 expression was found to be associated with poor prognosis for patients with GC. Collectively, this work found AARS1 with lactyltransferase activity in vitro and in vivo and revealed how the metabolite lactate is translated into a signal of cell proliferation.


Assuntos
Alanina-tRNA Ligase , Transdução de Sinais , Neoplasias Gástricas , Fatores de Transcrição , Proteínas de Sinalização YAP , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Aminoacil-tRNA Sintetases/metabolismo , Aminoacil-tRNA Sintetases/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Ácido Láctico/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Sinalização YAP/metabolismo , Proteínas de Sinalização YAP/genética , Alanina-tRNA Ligase/genética , Alanina-tRNA Ligase/metabolismo
6.
EMBO J ; 42(24): e114060, 2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38009297

RESUMO

Hepatocellular carcinoma (HCC) formation is a multi-step pathological process that involves evolution of a heterogeneous immunosuppressive tumor microenvironment. However, the specific cell populations involved and their origins and contribution to HCC development remain largely unknown. Here, comprehensive single-cell transcriptome sequencing was applied to profile rat models of toxin-induced liver tumorigenesis and HCC patients. Specifically, we identified three populations of hepatic parenchymal cells emerging during HCC progression, termed metabolic hepatocytes (HCMeta ), Epcam+ population with differentiation potential (EP+Diff ) and immunosuppressive malignant transformation subset (MTImmu ). These distinct subpopulations form an oncogenic trajectory depicting a dynamic landscape of hepatocarcinogenesis, with signature genes reflecting the transition from EP+Diff to MTImmu . Importantly, GPNMB+ Gal-3+ MTImmu cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 is required for the generation and malignant transformation of GPNMB+ Gal-3+ MTImmu cells. Enrichment of the GPNMB+ Gal-3+ MTImmu subset was found to be associated with poor prognosis and a higher rate of recurrence in patients. Collectively, we unraveled the single-cell HCC progression atlas and uncovered GPNMB+ Gal-3+ parenchymal cells as a major subset contributing to the immunosuppressive microenvironment thus malignance in HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Ratos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Hepatócitos , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Terapia de Imunossupressão , Microambiente Tumoral , Fatores de Transcrição SOXF , Glicoproteínas de Membrana/genética
7.
Cell Death Dis ; 14(9): 582, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37658050

RESUMO

Chemotherapy represents a major type of clinical treatment against colorectal cancer (CRC). Aberrant drug efflux mediated by transporters acts as a key approach for tumor cells to acquire chemotherapy resistance. Increasing evidence implies that tumor-associated macrophages (TAMs) play a pivotal role in both tumorigenesis and drug resistance. Nevertheless, the specific mechanism through which TAMs regulate drug efflux remains elusive. Here, we discovered that TAMs endow CRC cells with resistance to 5-fluorouracil (5-FU) treatment via a cell-cell interaction-mediated MRP1-dependent drug efflux process. Mechanistically, TAM-secreted C-C motif chemokine ligand 17 (CCL17) and CCL22, via membrane receptor CCR4, activated the PI3K/AKT pathway in CRC tumor cells. Specifically, phosphorylation of AKT inactivated IP3R and induced calcium aggregation in the ER, resulting in the activation of ATF6 and upregulation of GRP78. Accordingly, excessive GRP78 can interact with MRP1 and promote its translocation to the cell membrane, causing TAM-induced 5-FU efflux. Taken together, our results demonstrated that TAMs promote CRC chemotherapy resistance via elevating the expression of GRP78 to promote the membrane translocation of MRP1 and drug efflux, providing direct proof for TAM-induced drug resistance.


Assuntos
Neoplasias Colorretais , Chaperona BiP do Retículo Endoplasmático , Humanos , Macrófagos Associados a Tumor , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Fluoruracila/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fator 6 Ativador da Transcrição , Receptores CCR4 , Quimiocinas CXC
8.
J Hepatol ; 79(6): 1435-1449, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37689322

RESUMO

BACKGROUND & AIMS: Remodeling the tumor microenvironment is a critical strategy for treating advanced hepatocellular carcinoma (HCC). Yet, how distinct cell populations in the microenvironment mediate tumor resistance to immunotherapies, such as anti-PD-1, remains poorly understood. METHODS: We analyzed the transcriptomic profile, at a single-cell resolution, of tumor tissues from patients with HCC scheduled to receive anti-PD-1-based immunotherapy. Our comparative analysis and experimental validation using flow cytometry and histopathological analysis uncovered a discrete subpopulation of cells associated with resistance to anti-PD-1 treatment in patients and a rat model. A TurboID-based proximity labeling approach was deployed to gain mechanistic insights into the reprogramming of the HCC microenvironment. RESULTS: We identified CD10+ALPL+ neutrophils as being associated with resistance to anti-PD-1 treatment. These neutrophils exhibited a strong immunosuppressive activity by inducing an apparent "irreversible" exhaustion of T cells in terms of cell number, frequency, and gene profile. Mechanistically, CD10+ALPL+ neutrophils were induced by tumor cells, i.e., tumor-secreted NAMPT reprogrammed CD10+ALPL+ neutrophils through NTRK1, maintaining them in an immature state and inhibiting their maturation and activation. CONCLUSIONS: Collectively, our results reveal a fundamental mechanism by which CD10+ALPL+ neutrophils contribute to tumor immune escape from durable anti-PD-1 treatment. These data also provide further insights into novel immunotherapy targets and possible synergistic treatment regimens. IMPACT AND IMPLICATIONS: Herein, we discovered that tumor cells reprogrammed CD10+ALPL+ neutrophils to induce the "irreversible" exhaustion of T cells and hence allow tumors to escape from the intended effects of anti-PD-1 treatment. Our data provided a new theoretical basis for the elucidation of special cell populations and revealed a molecular mechanism underpinning resistance to immunotherapy. Targeting these cells alongside existing immunotherapy could be looked at as a potentially more effective therapeutic approach.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Ratos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linfócitos T , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neutrófilos , Imunoterapia/métodos , Microambiente Tumoral , Linfócitos T CD8-Positivos , Fosfatase Alcalina
9.
Theranostics ; 13(11): 3761-3780, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37441604

RESUMO

Rationale: Sepsis is a potentially life-threatening condition caused by the body's response to a severe infection. Although the identification of multiple pathways involved in inflammation, tissue damage and aberrant healing during sepsis, there remain unmet needs for the development of new therapeutic strategies essential to prevent the reoccurrence of infection and organ injuries. Methods: Expression of Suppressor of Fused (Sufu) was evaluated by qRT-PCR, western blotting, and immunofluorescence in murine lung and peritoneal macrophages. The significance of Sufu expression in prognosis was assessed by Kaplan-Meier survival analysis. The GFP-TRAF6-expressing stable cell line (GFP-TRAF6 Blue cells) were constructed to evaluate phase separation of TRAF6. Phase separation of TRAF6 and the roles of Sufu in repressing TRAF6 droplet aggregation were analyzed by co-immunoprecipitation, immunofluorescence, Native-PAGE, FRAP and in vitro assays using purified proteins. The effects of Sufu on sepsis-induced lung inflammation were evaluated by cell function assays, LPS-induced septic shock model and polymicrobial sepsis-CLP mice model. Results: We found that Sufu expression is reduced in early response to lipopolysaccharide (LPS)-induced acute inflammation in murine lung and peritoneal macrophages. Deletion of Sufu aggravated LPS-induced and CLP (cecal ligation puncture)-induced lung injury and lethality in mice, and augmented LPS-induced proinflammatory gene expression in cultured macrophages. In addition, we identified the role of Sufu as a negative regulator of the Toll-Like Receptor (TLR)-triggered inflammatory response. We further demonstrated that Sufu directly interacts with TRAF6, thereby preventing oligomerization and autoubiquitination of TRAF6. Importantly, TRAF6 underwent phase separation during LPS-induced inflammation, which is essential for subsequent ubiquitination activation and NF-κB activity. Sufu inhibits the phase-separated TRAF6 droplet formation, preventing NF-κB activation upon LPS stimulation. In a septic shock model, TRAF6 depletion rescued the augmented inflammatory phenotype in mice with myeloid cell-specific deletion of Sufu. Conclusions: These findings implicated Sufu as an important inhibitor of TRAF6 in sepsis and suggest that therapeutics targeting Sufu-TRAF6 may greatly benefit the treatment of sepsis.


Assuntos
Pneumonia , Sepse , Choque Séptico , Camundongos , Animais , NF-kappa B/metabolismo , Fator 6 Associado a Receptor de TNF , Lipopolissacarídeos/farmacologia , Inflamação , Sepse/tratamento farmacológico
11.
Acta Biochim Biophys Sin (Shanghai) ; 55(6): 893-903, 2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36924251

RESUMO

Gastric cancer (GC) is an aggressive malignant disease which still lacks effective early diagnosis markers and targeted therapies, representing the fourth-leading cause of cancer-associated death worldwide. The Hippo signaling pathway plays crucial roles in organ size control and tissue homeostasis under physiological conditions, yet its aberrations have been closely associated with several hallmarks of cancer. The last decade witnessed a burst of investigations dissecting how Hippo dysregulation contributes to tumorigenesis, highlighting the therapeutic potential of targeting this pathway for tumor intervention. In this review, we systemically document studies on the Hippo pathway in the contexts of gastric tumor initiation, progression, metastasis, acquired drug resistance, and the emerging development of Hippo-targeting strategies. By summarizing major open questions in this field, we aim to inspire further in-depth understanding of Hippo signaling in GC development, as well as the translational implications of targeting Hippo for GC treatment.


Assuntos
Via de Sinalização Hippo , Neoplasias Gástricas , Humanos , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Sinalização YAP , Fatores de Transcrição/metabolismo , Transformação Celular Neoplásica
12.
Protein Cell ; 14(7): 513-531, 2023 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-36921037

RESUMO

As an important part of tumor microenvironment, neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. Here we defined, at single-cell resolution, CD44-CXCR2- neutrophils as tumor-specific neutrophils (tsNeus) in both mouse and human gastric cancer (GC). We uncovered a Hippo regulon in neutrophils with unique YAP signature genes (e.g., ICAM1, CD14, EGR1) distinct from those identified in epithelial and/or cancer cells. Importantly, knockout of YAP/TAZ in neutrophils impaired their differentiation into CD54+ tsNeus and reduced their antitumor activity, leading to accelerated GC progression. Moreover, the relative amounts of CD54+ tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Interestingly, GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+ tsNeus. Furthermore, pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC, with no significant inflammation-related side effects. Thus, our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus, opening a new possibility to develop neutrophil-based antitumor therapeutics.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Neoplasias Gástricas , Humanos , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias Gástricas/patologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Transdução de Sinais/genética , Proteínas de Sinalização YAP , Microambiente Tumoral , Receptores de Hialuronatos/genética
13.
Am J Cancer Res ; 13(12): 5981-5995, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38187053

RESUMO

Porphyromonas gingivalis (P. gingivalis), a Gram-negative oral anaerobe, was demonstrated to facilitate colonization and progression in colonic tumor, while the underlying mechanism still remains to be clarified. Here, we identified the proteome profile changed by P. gingivalis infection in HCT116 cells through label-free quantitative proteomics, and found that deubiquitinase UCHL3 was a key protein that response for P. gingivalis infection. By CCK8, colony formation, wound healing assays, and in vivo subcutaneous tumor mouse moudle, we proved that P. gingivalis could promote the proliferation and migration of colon cancer, while the process was inhibited by UCHL3 knock down. Through IP-MS, we identified GNG12 as the UCHL3 interacting protein. The protein level of GNG12 was significantly reduced when knock out UCHL3. Thus we propose that GNG12 is a substrate protein of UCHL3. Furthermore, we demonstrated that overexpression of GNG12 could restore the tumor inhibition effect caused by UCHL3 knock down, and UCHL3-GNG12 axis promote colon cancer progression via the NF-κB signal pathway. Collectively, this study unveiled that P. gingivalis infection up-regulated UCHL3 and stabilized its substrate protein GNG12 to activate the NF-κB signal pathway to promote colon cancer progression. Our study indicate that UCHL3 is a potential biomarker and therapeutic target for colon cancer which infected with P. gingivalis.

14.
Adv Sci (Weinh) ; 9(22): e2201711, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35603970

RESUMO

Tumor targeting and effective immunomodulation are of critical significance during tumor treatment by sonodynamic therapy (SDT). Herein, the probiotic engineering of the clinically approved sonosensitizer (hematoporphyrin monomethyl ether (HMME)) is reported onto the probiotic bacterium Bifidobacteria Longum (BiL) for sonosensitive bifidobacterium construction (HMME@BiL cells). Based on the hypoxic tropism feature of the strain, effective tumor-targeted sonodynamic therapeutics can be achieved both in vitro and in vivo. To improve the immunological responses against tumor during sonodynamics, a recently-developed stimulator of interferon genes immune agonist SR717 has been employed to improve the anti-tumor immunity with prominent activities, eradicating both primary and metastatic tumors with high efficiency and satisfied biocompatibility. The present work provides a promising paradigm of microbiotic nanomedicine in a sophisticated sonoimmunotherapeutic strategy against malignant tumors.


Assuntos
Neoplasias , Probióticos , Terapia por Ultrassom , Humanos , Neoplasias/terapia , Probióticos/uso terapêutico
15.
Front Cell Dev Biol ; 10: 817831, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35309941

RESUMO

The spindle assembly checkpoint (SAC) is a critical monitoring device in mitosis for the maintenance of genomic stability. Specifically, the SAC complex comprises several factors, including Mad1, Mad2, and Bub1. Ataxia-telangiectasia mutated (ATM) kinase, the crucial regulator in DNA damage response (DDR), also plays a critical role in mitosis by regulating Mad1 dimerization and SAC. Here, we further demonstrated that ATM negatively regulates the phosphorylation of Mad2, another critical component of the SAC, which is also involved in DDR. Mechanistically, we found that phosphorylation of Mad2 is aberrantly increased in ATM-deficient cells. Point-mutation analysis further revealed that Serine 195 mainly mediated Mad2 phosphorylation upon ATM ablation. Functionally, the phosphorylation of Mad2 causes decreased DNA damage repair capacity and is related to the resistance to cancer cell radiotherapy. Altogether, this study unveils the key regulatory role of Mad2 phosphorylation in checkpoint defects and DNA damage repair in ATM-deficient cells.

16.
J Clin Invest ; 132(9)2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35290241

RESUMO

The striatin-interacting phosphatase and kinase (STRIPAK) complexes integrate extracellular stimuli that result in intracellular activities. Previously, we discovered that STRIPAK is a key machinery responsible for loss of the Hippo tumor suppressor signal in cancer. Here, we identified the Hippo-STRIPAK complex as an essential player in the control of DNA double-stranded break (DSB) repair and genomic stability. Specifically, we found that the mammalian STE20-like protein kinases 1 and 2 (MST1/2), independent of classical Hippo signaling, directly phosphorylated zinc finger MYND type-containing 8 (ZMYND8) and hence resulted in the suppression of DNA repair in the nucleus. In response to genotoxic stress, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway was determined to relay nuclear DNA damage signals to the dynamic assembly of Hippo-STRIPAK via TANK-binding kinase 1-induced (TBK1-induced) structural stabilization of the suppressor of IKBKE 1- sarcolemma membrane-associated protein (SIKE1-SLMAP) arm. As such, we found that STRIPAK-mediated MST1/2 inactivation increased the DSB repair capacity of cancer cells and endowed these cells with resistance to radio- and chemotherapy and poly(ADP-ribose)polymerase (PARP) inhibition. Importantly, targeting the STRIPAK assembly with each of 3 distinct peptide inhibitors efficiently recovered the kinase activity of MST1/2 to suppress DNA repair and resensitize cancer cells to PARP inhibitors in both animal- and patient-derived tumor models. Overall, our findings not only uncover what we believe to be a previously unrecognized role for STRIPAK in modulating DSB repair but also provide translational implications of cotargeting STRIPAK and PARP for a new type of synthetic lethality anticancer therapy.


Assuntos
Neoplasias Gastrointestinais , Monoéster Fosfórico Hidrolases , Animais , Humanos , Mamíferos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Transdução de Sinais/fisiologia , Mutações Sintéticas Letais , Fatores de Transcrição
17.
Cell Res ; 32(4): 359-374, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35197608

RESUMO

TSPAN family of proteins are generally considered to assemble as multimeric complexes on the plasma membrane. Our previous work uncovered that TSPAN8 can translocate into the nucleus as a membrane-free form, a process that requires TSPAN8 palmitoylation and association with cholesterol to promote its extraction from the plasma membrane and subsequent binding with 14-3-3θ and importin-ß. However, what upstream signal(s) regulate(s) the nuclear translocation of TSPAN8, the potential function of TSPAN8 in the nucleus, and the underlying molecular mechanisms all remain unclear. Here, we demonstrate that, epidermal growth factor receptor (EGFR) signaling induces TSPAN8 nuclear translocation by activating the kinase AKT, which in turn directly phosphorylates TSPAN8 at Ser129, an event essential for its binding with 14-3-3θ and importin ß1. In the nucleus, phosphorylated TSPAN8 interacts with STAT3 to enhance its chromatin occupancy and therefore regulates transcription of downstream cancer-promoting genes, such as MYC, BCL2, MMP9, etc. The EGFR-AKT-TSPAN8-STAT3 axis was found to be hyperactivated in multiple human cancers, and associated with aggressive phenotype and dismal prognosis. We further developed a humanized monoclonal antibody hT8Ab4 that specifically recognizes the large extracellular loop of TSPAN8 (TSPAN8-LEL), thus being able to block the extraction of TSPAN8 from the plasma membrane and consequently its nuclear localization. Importantly, both in vitro and in vivo studies demonstrated an antitumor effect of hT8Ab4. Collectively, we discovered an unconventional function of TSPAN8 and dissected the underlying molecular mechanisms, which not only showcase a new layer of biological complexity of traditional membrane proteins, but also shed light on TSPAN8 as a novel therapeutic target for refractory cancers.


Assuntos
Receptores ErbB , Neoplasias , Fator de Transcrição STAT3 , Tetraspaninas , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Neoplasias/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Tetraspaninas/genética , Tetraspaninas/metabolismo
18.
IEEE Trans Cybern ; 52(3): 1575-1587, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32471807

RESUMO

This article investigates the problem of secure state estimation for continuous-time linear systems in the presence of sparse sensor attacks. Compared with the existing results, the attacked sensor set can be changed by adversaries against secure estimation. To address the more erratic attacks, a novel supervisory state observer is proposed, which employs a bank of candidate nonlinear subobservers and a switching logic administrated by a monitoring function to select the active subobserver at every instant of time. Based on the stability analysis of switched systems, it is proven that the supervisory observer asymptotically converges to a neighborhood of the true system state in the presence of the sensor attacks and bounded disturbances. A simulation example is given to substantiate the theoretical results.

20.
Adv Sci (Weinh) ; 8(17): e2004850, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34240584

RESUMO

Elevated Wnt/ß-catenin signaling has been commonly associated with tumorigenesis especially colorectal cancer (CRC). Here, an MST4-pß-cateninThr40 signaling axis essential for intestinal stem cell (ISC) homeostasis and CRC development is uncovered. In response to Wnt3a stimulation, the kinase MST4 directly phosphorylates ß-catenin at Thr40 to block its Ser33 phosphorylation by GSK3ß. Thus, MST4 mediates an active process that prevents ß-catenin from binding to and being degraded by ß-TrCP, leading to accumulation and full activation of ß-catenin. Depletion of MST4 causes loss of ISCs and inhibits CRC growth. Mice bearing either MST4T178E mutation with constitutive kinase activity or ß-cateninT40D mutation mimicking MST4-mediated phosphorylation show overly increased ISCs/CSCs and exacerbates CRC. Furthermore, the MST4-pß-cateninThr40 axis is upregulated and correlated with poor prognosis of human CRC. Collectively, this work establishes a previously undefined machinery for ß-catenin activation, and further reveals its function in stem cell and tumor biology, opening new opportunities for targeted therapy of CRC.


Assuntos
Carcinogênese/genética , Neoplasias Colorretais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/metabolismo , Animais , Neoplasias Colorretais/genética , Modelos Animais de Doenças , Feminino , Humanos , Intestinos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/genética , Células-Tronco/metabolismo , beta Catenina/genética
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