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2.
Org Biomol Chem ; 19(39): 8487-8491, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34545904

RESUMO

An efficient and practical approach for the synthesis of medicinally important acridones was developed from anthranils and commercially available arylboronic acids by a tandem copper(I)-catalyzed electrophilic amination/Ag(I)-mediated oxidative annulation strategy. This new and straightforward protocol displayed a broad substrate scope (25 examples) and high functional group tolerance. What's more, a possible mechanistic proposal was also presented.

3.
Cancers (Basel) ; 13(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919420

RESUMO

As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), and the Wnt/ß-catenin pathway, as well as the dynamics of exosome and cellular metabolism. Finally, we discuss the implications of the highly plastic nature and epigenetic susceptibility of CD151 expression, function, and signaling for clinical diagnosis and therapeutic intervention for human cancer.

4.
Food Chem ; 354: 129511, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-33735695

RESUMO

Based on the successful synthesis of mercaptomethamidophos as a substrate, a novel nanogold/mercaptomethamidophos multi-residue electrochemical biosensor was designed and fabricated by combining nanoscale effect, strong Au-S bonds as well as interaction between acetylcholinesterase (AChE) and mercaptomethamidophos, which can simultaneously detect 11 kinds of organophosphorus pesticides (OPPs) and total amount of OPPs using indirect competitive method. Electrochemical behavior of the modified electrode was characterized by differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). The AChE concentration and incubation time were optimized at 37.4 °C to achieve the best detection effect. This biosensor exhibits excellent electrochemical properties with a wider linear range of 0.1 ~ 1500 ng·mL-1, lower detection limit of 0.019 ~ 0.077 ng·mL-1, better stability and repeatability, which realizes the rapid detection of total amount of OPPs, and can simultaneously detect a large class of OPPs rather than one kind of OPP. Two OPPs (trichlorfon, dichlorvos) were detected in actual samples of apple and cabbage and achieved satisfactory test results.


Assuntos
Técnicas Biossensoriais/métodos , Nanopartículas Metálicas/química , Compostos Organofosforados/química , Compostos Organotiofosforados/química , Praguicidas/análise , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Brassica/química , Brassica/metabolismo , Espectroscopia Dielétrica , Eletrodos , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Ouro/química , Limite de Detecção
6.
Cancer Res ; 81(3): 552-566, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33229341

RESUMO

Cancer cells need to generate large amounts of glutathione (GSH) to buffer oxidative stress during tumor development. A rate-limiting step for GSH biosynthesis is cystine uptake via a cystine/glutamate antiporter Xc-. Xc- is a sodium-independent antiporter passively driven by concentration gradients from extracellular cystine and intracellular glutamate across the cell membrane. Increased uptake of cystine via Xc- in cancer cells increases the level of extracellular glutamate, which would subsequently restrain cystine uptake via Xc-. Cancer cells must therefore evolve a mechanism to overcome this negative feedback regulation. In this study, we report that glutamate transporters, in particular SLC1A1, are tightly intertwined with cystine uptake and GSH biosynthesis in lung cancer cells. Dysregulated SLC1A1, a sodium-dependent glutamate carrier, actively recycled extracellular glutamate into cells, which enhanced the efficiency of cystine uptake via Xc- and GSH biosynthesis as measured by stable isotope-assisted metabolomics. Conversely, depletion of glutamate transporter SLC1A1 increased extracellular glutamate, which inhibited cystine uptake, blocked GSH synthesis, and induced oxidative stress-mediated cell death or growth inhibition. Moreover, glutamate transporters were frequently upregulated in tissue samples of patients with non-small cell lung cancer. Taken together, active uptake of glutamate via SLC1A1 propels cystine uptake via Xc- for GSH biosynthesis in lung tumorigenesis. SIGNIFICANCE: Cellular GSH in cancer cells is not only determined by upregulated Xc- but also by dysregulated glutamate transporters, which provide additional targets for therapeutic intervention.


Assuntos
Cistina/metabolismo , Transportador 3 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Glutationa/biossíntese , Neoplasias Pulmonares/metabolismo , Animais , Antiporters/metabolismo , Morte Celular , Linhagem Celular Tumoral , Glutamina/deficiência , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Estresse Oxidativo , Receptores Acoplados a Proteínas G , Estresse Fisiológico , Regulação para Cima
7.
Cell Oncol (Dordr) ; 43(6): 1049-1066, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33006750

RESUMO

PURPOSE: Stemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a transcriptional and epigenetic mediator, for TNBC. METHODS: Two independent patient cohorts were subjected to bioinformatic and IHC examination for clinical association of candidate cancer drivers. The efficacy and biological bases for co-targeting these drivers were interrogated using cancer cell lines, a protein kinase array, chemical inhibitors, RNAi/CRISPR/Cas9 approaches, and a 4 T1-Balb/c xenograft model. RESULTS: We found that amplification of the chromosome 8q24 region occurred in nearly 20% of TNBC tumors, and that it coincided with co-upregulation or amplification of c-Myc and FAK, a key effector of integrin-dependent signaling. This co-upregulation at the mRNA or protein level correlated with a poor patient survival (p < 0.0109 or p < 0.0402, respectively). Furthermore, we found that 14 TNBC cell lines exhibited high vulnerabilities to the combination of JQ1 and VS-6063, potent pharmacological antagonists of the BRD4/c-Myc and integrin/FAK-dependent pathways, respectively. We also observed a cooperative inhibitory effect of JQ1 and VS-6063 on tumor growth and infiltration of Ly6G+ myeloid-derived suppressor cells in vivo. Finally, we found that JQ1 and VS-6063 cooperatively induced apoptotic cell death by altering XIAP, Bcl2/Bcl-xl and Bim levels, impairing c-Src/p130Cas-, PI3K/Akt- and RelA-associated signaling, and were linked to EMT-inducing transcription factor Snail- and Slug-dependent regulation. CONCLUSION: Based on our results, we conclude that the BRD4/c-Myc- and integrin/FAK-dependent pathways act in concert to promote breast cancer cell survival and poor clinical outcomes. As such, they represent promising targets for a synthetic lethal-type of therapy against TNBC.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Integrinas/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Azepinas/farmacologia , Proteína 11 Semelhante a Bcl-2/metabolismo , Benzamidas/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirazinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
8.
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
9.
Am J Transl Res ; 12(4): 1428-1442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32355552

RESUMO

Owing to the complexity of interacting molecular networks on the cell surface, integrin-associated tetraspanin CD151 remains controversial regarding its clinical importance and functional impact in prostate cancer. The current study evaluated dynamics and clinical importance of CD151 expression and its function in prostate cancer by IHC analysis of two independent patient cohorts (n=80, 181), bioinformatic interrogation of the TCGA database, and evaluation of gene knockdown effect at the cellular level. Our data showed that aside from high mRNA expression, CD151 was primarily localized to intercellular junctions at the plasma membrane in normal prostate glands or benign tissues, regardless of nature of antibodies used. By contrast, in primary tumors from patients with metastatic disease, CD151 was largely localized in the cytosol. Furthermore, the level of the cell-cell junction-linked CD151 was inversely associated with Gleason grade and tumor stage (P<0.001 for both). The portion of primary tumors expressing junctional CD151 was also three-fold less in the metastatic patient population than its counterpart (P<0.001). In line with these observations, CD151 and its associated α3ß1 or α6ß4 integrin inversely correlated with androgen receptor (AR) at the mRNA level (Spearman coefficient: -0.44, -0.48 and -0.42) in the TCGA cohort. Expression of these adhesion molecules also correlated with DNA methylation in their promoters (Spearman coefficient: -0.37, -0.71 and -0.82). Combined, these data suggest that CD151 and associated integrins are linked to tumor metastasis through AR and the epigenetic program. Meanwhile, CD151 knockdown in E-cadherin-positive tumor cells led to increased cell proliferation and induction of the epithelial-mesenchymal transition (EMT)-like phenotype. Given the strong RGD-binding integrin dependence of EMT-featured tumor cells, we examined focal adhesion kinase (FAK), their key signaling effector, in the above patient cohorts. In contrast to CD151, FAK exhibited positive correlation with tumor grade and stage as well as AR and p53 inactivation at either mRNA, protein or genomic level. Taken together, our results suggest that CD151 represses prostate cancer by antagonizing cell proliferation, EMT and the signaling of RGD-binding integrins. Since this anti-tumorigenic role is prone to the AR-mediated transcriptional and epigenetic regulation, CD151 and possibly α3ß1 and α6ß4 integrins are of potential biomarkers for metastatic prostate cancer.

10.
Nat Rev Mol Cell Biol ; 21(6): 341-352, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32300252

RESUMO

Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.


Assuntos
Pesquisa Biomédica/normas , Transição Epitelial-Mesenquimal , Animais , Movimento Celular , Plasticidade Celular , Consenso , Biologia do Desenvolvimento/normas , Humanos , Neoplasias/patologia , Terminologia como Assunto
11.
Genes Dis ; 7(2): 172-184, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32215287

RESUMO

Epithelial-mesenchymal Transition (EMT) is a de-differentiation program that imparts tumor cells with the phenotypic and cellular plasticity required for drug resistance, metastasis, and recurrence. This dynamic and reversible events is governed by a network of EMT-transcription factors (EMT-TFs) through epigenetic regulation. Many chromatin modifying-enzymes utilize metabolic intermediates as cofactors or substrates; this suggests that EMT is subjected to the metabolic regulation. Conversely, EMT rewires metabolic program to accommodate cellular changes during EMT. Here we summarize the latest findings regarding the epigenetic regulation of EMT, and discuss the mutual interactions among metabolism, epigenetic regulation, and EMT. Finally, we provide perspectives of how this interplay contributes to cellular plasticity, which may result in the clinical manifestation of tumor heterogeneity.

12.
Proc Natl Acad Sci U S A ; 117(7): 3748-3758, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32015106

RESUMO

Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell-platelet interaction. Using rescue experiments and functional blocking antibodies, we identified type I collagen as the key mediator of Hsp47-induced cancer cell-platelet interaction. We also found that Hsp47-dependent collagen deposition and platelet recruitment facilitated cancer cell clustering and extravasation in vitro. By analyzing DNA/RNA sequencing data generated from human breast cancer tissues, we showed that gene amplification and increased expression of Hsp47 were associated with cancer metastasis. These results suggest that targeting the Hsp47/collagen axis is a promising strategy to block cancer cell-platelet interaction and cancer colonization in secondary organs.


Assuntos
Plaquetas/metabolismo , Neoplasias da Mama/metabolismo , Colágeno/metabolismo , Proteínas de Choque Térmico HSP47/metabolismo , Células Neoplásicas Circulantes/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Transição Epitelial-Mesenquimal , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Amplificação de Genes , Proteínas de Choque Térmico HSP47/genética , Humanos , Camundongos SCID , Metástase Neoplásica
13.
Oncogene ; 39(15): 3179-3194, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32060421

RESUMO

Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE2 signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE2 signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE2 signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.


Assuntos
Dinoprostona/metabolismo , Neoplasias Pulmonares/imunologia , Prostaglandina-E Sintases/metabolismo , Receptores Acoplados a Proteínas G/genética , Evasão Tumoral/genética , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , 4-Butirolactona/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Knockout , Camundongos Nus , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/patologia , Cultura Primária de Células , Prostaglandina-E Sintases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
14.
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
15.
Cancer Res ; 80(4): 784-797, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31848193

RESUMO

Cancer cells that succeed in forming metastasis need to be reprogrammed to evade immune surveillance and survive in a new microenvironment. This is facilitated by metastatic niches that are either postformed through reciprocal signaling between tumor cells and local stromal cells or preformed as premetastatic niches before tumor cell arrival. IL6/STAT3 signaling is aberrantly activated in lung tumorigenesis and metastasis, however, the roles and mechanisms of action of IL6 remain controversial. Here, we showed that blockade of intrinsic STAT3 signaling in lung tumor cells suppressed lung metastasis in immune-competent syngeneic mice, but not in immune-deficient nude mice. Consistently, repression of STAT3 signaling in tumor cells made them susceptible to T-cell-mediated cytotoxicity. Thus, STAT3-mediated immunosuppression is crucial for metastasis. Noticeably, lung metastasis was greatly increased in Gprc5a-knockout (ko; 5a -/-) mice compared with wild-type mice, which correlated with upregulated IL6 in the tumor microenvironment. Depletion of IL6 via combined deletion of Il6 and Gprc5a genes almost completely eliminated lung metastasis in Gprc5a-ko/Il6-ko (5a -/-;Il6 -/-) mice. Mechanistically, dysregulated IL6 reprogrammed the STAT3 pathway in metastatic tumor cells, and induced recruitment of myeloid-derived suppressor cells and polarized macrophages to evade host immunity. Consistently, IHC staining showed that activated STAT3 correlated with repressed infiltration of CD8+ T cells in non-small cell lung cancer. Therefore, IL6/STAT3 signaling is crucial for orchestrating premetastatic niche formation and immunosuppression in lung.Significance: IL6 plays important roles not only in cell autonomous propensity for metastasis, but also in establishing the metastatic niche.


Assuntos
Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Linhagem Celular Tumoral , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Camundongos Nus , Células Supressoras Mieloides/imunologia , Cultura Primária de Células , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Fator de Transcrição STAT3/imunologia , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
16.
Genes Dis ; 6(4): 333-334, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31832512

RESUMO

Metabolic abnormalities are emerging as an active driver to the development, progression and metastasis of various tumors. In the recent issue of the EMBO Journal, Yang and colleagues identified that succinylacetone (SA) could act as an oncometabolite and that accumulation of SA activates the NRF2/IGF1R axis in hepatocellular carcinoma (HCC) development. These discoveries not only yield great insights in the understanding of tumor biology, but also hold significant clinical ramifications, as these findings may pave a new way for the early diagnosis and treatment of HCC.

17.
Neoplasia ; 21(12): 1151-1163, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31783316

RESUMO

Tetraspanin CD151 is increasingly implicated as a multifaceted mediator of cancer development and progression. Here we investigated the role of CD151 in breast cancer in the context of the Wnt oncogenic activation. Our data showed that removal of one or both of CD151 alleles in the MMTV-Wnt1 model significantly decreased the tumor-free survival of mice from 34 weeks on average to 22 weeks and 18 weeks, respectively. This effect coincided with an accelerated tumor growth and an increased number of Ki-67+ proliferative cells. Mechanistically, the CD151-deficient tumors were largely ER+, and exhibited hyperactivation of the Wnt pathway as reflected by a marked upregulation in ß-catenin and Cyclin D1, and their target genes. In addition, E-cadherin displayed a cytosolic distribution and transcription factor Snail was markedly upregulated. Collectively, this data implies that CD151 suppresses the Wnt1-driven tumorigenesis, at least in part, via counteracting the epithelial-mesenchymal transition (EMT)-like program in luminal epithelial cells. Meanwhile, the proportion of tumor cells expressing CK5 or p63, the biomarkers of myoepithelial/basal cells, markedly decreased in the absence of CD151. This change was accompanied by a decreased invasiveness of tumors and their incompetence to form a long-term cell culture. Consistent with this basal cell-linked role, the CD151 downregulation impairs mammosphere formation in MCF-10A cells and the defect was rescued by re-expression of intact CD151 ORF, but not its integrin binding-defective mutant. Overall, our study suggests that CD151 is a key player in the Wnt oncogene-driven tumorigenesis and impacts breast cancer malignancy in a cell type-dependent manner.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Deleção de Genes , Tetraspanina 24/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Mamárias Animais , Vírus do Tumor Mamário do Camundongo , Camundongos , Transdução de Sinais , Proteína Wnt1/genética , Proteína Wnt1/metabolismo
18.
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
19.
Am J Cancer Res ; 9(6): 1145-1160, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31285948

RESUMO

Early metastasis and local recurrence are the major causes of mortality and poor prognosis of non-small cell lung cancer (NSCLC). However, the underlying mechanisms of these processes are poorly understood. In this study, we aimed to investigate the roles of the PTGES/PGE2 pathway in lung cancer progression. We found that prostaglandin E synthase (PTGES), a key enzyme for PGE2 synthesis in the arachidonic acid pathway, was highly dysregulated in NSCLC. Dysregulated PTGES was essential for the promotion of tumor migration and metastasis of NSCLC cells. Knockdown of PTGES in lung cancer cells resulted in suppressed cell migration, which was reversed by exogenous PGE2. Consistent with this, PTGES knockdown also reduced the expression of CSC markers, tumor sphere formation, colony forming activity, tumorigenicity, and lung metastasis in vivo. Dysregulated PTGES is mainly attributed to protein stabilization by USP9X, a deubiquitination enzyme. USP9X physically interacted with PTGES and prevented it from proteasome-directed degradation via deubiquitination. Consistent with this, USP9X expression was highly correlated with PTGES expression in NSCLC tumor tissues. Taken together, our results show that the upregulated USP9X-PTGES-PGE2 axis contributes significantly to the metastatic features of NSCLC.

20.
J Clin Invest ; 129(3): 1030-1046, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30688660

RESUMO

Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress-induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A-dependent (LDHA-dependent) metabolic rewiring. Chronic stress-induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress-induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , Epinefrina/metabolismo , L-Lactato Desidrogenase/metabolismo , Células-Tronco Neoplásicas/enzimologia , Estresse Psicológico/metabolismo , Animais , Ácido Ascórbico/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia
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