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2.
J Cancer Res Clin Oncol ; 150(5): 253, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38748285

RESUMO

BACKGROUND: Lysine-specific demethylase 1 (LSD1) is highly expressed in a variety of malignant tumors, rendering it a crucial epigenetic target for anti-tumor therapy. Therefore, the inhibition of LSD1 activity has emerged as a promising innovative therapeutic approach for targeted cancer treatment. METHODS: In our study, we employed innovative structure-based drug design methods to meticulously select compounds from the ZINC15 database. Utilizing virtual docking, we evaluated docking scores and binding modes to identify potential inhibitors. To further validate our findings, we harnessed molecular dynamic simulations and conducted meticulous biochemical experiments to deeply analyze the binding interactions between the protein and compounds. RESULTS: Our results showcased that ZINC10039815 exhibits an exquisite binding mode with LSD1, fitting perfectly into the active pocket and forming robust interactions with multiple critical residues of the protein. CONCLUSIONS: With its significant inhibitory effect on LSD1 activity, ZINC10039815 emerges as a highly promising candidate for the development of novel LSD1 inhibitors.


Assuntos
Inibidores Enzimáticos , Histona Desmetilases , Simulação de Acoplamento Molecular , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Histona Desmetilases/química , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Simulação de Dinâmica Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
3.
Int J Surg ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38781035

RESUMO

BACKGROUND: Sleep problems are prevalent. However, the impact of sleep patterns on digestive diseases remains uncertain. Moreover, the interaction between sleep patterns and genetic predisposition with digestive diseases has not been comprehensively explored. METHODS: 410,586 participants from UK Biobank with complete sleep information were included in the analysis. Sleep patterns were measured by sleep scores as the primary exposure, based on five healthy sleep behaviors. Individual sleep behaviors were secondary exposures. Genetic risk of the digestive diseases was characterized by polygenic risk score. Primary outcome was incidence of 16 digestive diseases. RESULTS: Healthy sleep scores showed dose-response associations with reduced risks of digestive diseases. Compared to participants scoring 0-1, those scoring 5 showed a 28% reduced risk of any digestive disease, including a 50% decrease in irritable bowel syndrome, 37% in non-alcoholic fatty liver disease, 35% in peptic ulcer, 34% in dyspepsia, 32% in gastroesophageal reflux disease, 28% in constipation, 25% in diverticulosis, 24% in severe liver disease, and 18% in gallbladder disease, whereas no correlation was observed with inflammatory bowel disease and pancreatic disease. Participants with poor sleep and high genetic risk exhibited approximately a 60% increase in the risk of digestive diseases. A healthy sleep pattern is linked to lower digestive disease risk in participants of all genetic risk levels. CONCLUSIONS: In this large population-based cohort, a healthy sleep pattern was associated with reduced risk of digestive diseases, regardless of the genetic susceptibility. Our findings underscore the potential impact of healthy sleep traits in mitigating the risk of digestive diseases.

4.
Nat Commun ; 15(1): 2039, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448420

RESUMO

Reversible protein phosphorylation, regulated by protein phosphatases, fine-tunes target protein function and plays a vital role in biological processes. Dysregulation of this process leads to aberrant post-translational modifications (PTMs) and contributes to disease development. Despite the widespread use of artificial catalysts as enzyme mimetics, their direct modulation of proteins remains largely unexplored. To address this gap and enable the reversal of aberrant PTMs for disease therapy, we present the development of artificial protein modulators (APROMs). Through atomic-level engineering of heterogeneous catalysts with asymmetric catalytic centers, these modulators bear structural similarities to protein phosphatases and exhibit remarkable ability to destabilize the bridging µ3-hydroxide. This activation of catalytic centers enables spontaneous hydrolysis of phospho-substrates, providing precise control over PTMs. Notably, APROMs, with protein phosphatase-like characteristics, catalytically reprogram the biological function of α-synuclein by directly hydrolyzing hyperphosphorylated α-synuclein. Consequently, synaptic function is reinforced in Parkinson's disease. Our findings offer a promising avenue for reprogramming protein function through de novo PTMs strategy.


Assuntos
Ursidae , alfa-Sinucleína , Animais , alfa-Sinucleína/genética , Catálise , Engenharia , Hidrólise , Fosfoproteínas Fosfatases/genética
5.
Adv Sci (Weinh) ; 11(6): e2307389, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38064201

RESUMO

Cancer therapeutic vaccines are powerful tools for immune system activation and eliciting protective responses against tumors. However, their efficacy has often been hindered by weak and slow immune responses. Here, the authors introduce an immunization strategy employing senescent erythrocytes to facilitate the accumulation of immunomodulatory zinc-Alum/ovalbumin (ZAlum/OVA) nanovaccines within both the spleen and solid tumors by temporarily saturating liver macrophages. This approach sets the stage for boosted cancer metalloimmunotherapy through a cascade immune activation. The accumulation of ZAlum/OVA nanovaccines in the spleen substantially enhances autophagy-dependent antigen presentation in dendritic cells, rapidly initiating OVA-specific T-cell responses against solid tumors. Concurrently, ZAlum/OVA nanovaccines accumulated in the tumor microenvironment trigger immunogenic cell death, leading to the induction of individualized tumor-associated antigen-specific T cell responses and increased T cell infiltration. This erythrocyte-assisted cascade immune activation using ZAlum/OVA nanovaccines results in rapid and robust antitumor immunity induction, holding great potential for clinical cancer metalloimmunotherapy.


Assuntos
Compostos de Alúmen , Vacinas Anticâncer , Neoplasias , Humanos , Ovalbumina , Nanovacinas , Neoplasias/tratamento farmacológico , Apresentação de Antígeno , Zinco , Microambiente Tumoral
6.
Adv Healthc Mater ; 12(31): e2302111, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37699592

RESUMO

Photothermal immunotherapy (PTI) has emerged as a promising approach for cancer treatment, while its efficacy is often hindered by the immunosuppressive tumor microenvironment (TME). Here, this work presents a multifunctional platform for tumor PTI based on ruthenium nanocrystal-decorated mesoporous silica nanoparticles (RuNC-MSN). By precisely regulating the distance between RuNC on MSN, this work achieves a remarkable enhancement in surface plasmon resonance of RuNC, leading to a significant improvement in the photothermal efficiency of RuNC-MSN. Furthermore, the inherent catalase-like activity of RuNC-MSN enables effective modulation of the immunosuppressive TME, thereby facilitating an enhanced immune response triggered by the photothermal effect-mediated immunogenic cell death (ICD). As a result, RuNC-MSN exhibits superior PTI performance, resulting in pronounced inhibition of primary tumor and metastasis. This study highlights the rational design of PTI agents with coupling effect-enhanced surface plasmon resonance, enabling simultaneous induction of ICD and regulation of the immunosuppressive TME, thereby significantly boosting PTI efficacy.


Assuntos
Nanopartículas , Neoplasias , Rutênio , Humanos , Dióxido de Silício/farmacologia , Doxorrubicina/farmacologia , Ressonância de Plasmônio de Superfície , Neoplasias/patologia , Imunoterapia , Microambiente Tumoral , Linhagem Celular Tumoral
8.
Cancer Res ; 83(19): 3220-3236, 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37463119

RESUMO

Resistance to endocrine therapy represents a major concern for patients with estrogen receptor α-positive (ERα+) breast cancer. Endocrine therapy resistance is commonly mediated by activated E2F signaling. A better understanding of the mechanisms governing E2F1 activity in resistant cells could reveal strategies for overcoming resistance. Here, we identified the long noncoding RNA (lncRNA) actin gamma 1 pseudogene 25 (AGPG) as a regulator of E2F1 activity in endocrine-resistant breast cancer. Expression of AGPG was increased in endocrine-resistant breast cancer cells, which was driven by epigenomic activation of an enhancer. AGPG was also abnormally upregulated in patient breast tumors, especially in the luminal B subtype, and high AGPG expression was associated with poor survival of patients with ERα+ breast cancer receiving endocrine therapy. The upregulation of AGPG mediated resistance to endocrine therapy and cyclin-dependent kinase 4/6 inhibition in breast cancer cells. Mechanistically, AGPG physically interacted with PURα, thus releasing E2F1 from PURα and leading to E2F1 signaling activation in ERα+ breast cancer cells. In patients with breast cancer, E2F1 target genes were positively and negatively correlated with expression of AGPG and PURα, respectively. Coadministration of chemically modified AGPG siRNA and tamoxifen strongly suppressed tumor growth in endocrine-resistant cell line-derived xenografts. Together, these results demonstrate that AGPG can drive endocrine therapy resistance and indicate that it is a promising biomarker and potential therapeutic target in breast cancer. SIGNIFICANCE: Blockade of formation of the PURα/E2F1 complex by lncRNA AGPG activates E2F1 and promotes endocrine resistance, providing potential strategies for combatting endocrine-resistant breast cancer.

9.
Int J Mol Sci ; 24(6)2023 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-36982338

RESUMO

The WD40 repeat-containing F-box proteins (FBXWs) family belongs to three major classes of F-box proteins. Consistent with the function of other F-box proteins, FBXWs are E3 ubiquitin ligases to mediate protease-dependent protein degradation. However, the roles of several FBXWs remain elusive. In the present study, via integrative analysis of transcriptome profiles from The Cancer Genome Atlas (TCGA) datasets, we found that FBXW9 was upregulated in the majority of cancer types, including breast cancer. FBXW expression was correlated with the prognosis of patients with various types of cancers, especially for FBXW4, 5, 9, and 10. Moreover, FBXWs were associated with infiltration of immune cells, and expression of FBXW9 was associated with poor prognosis of patients receiving anti-PD1 therapy. We predicted several substrates of FBXW9, and TP53 was the hub gene in the list. Downregulation of FBXW9 increased the expression of p21, a target of TP53, in breast cancer cells. FBXW9 was also strongly correlated with cancer cell stemness, and genes correlated with FBXW9 were associated with several MYC activities according to gene enrichment analysis in breast cancer. Cell-based assays showed that silencing of FBXW9 inhibited cell proliferation and cell cycle progression in breast cancer cells. Our study highlights the potential role of FBXW9 as a biomarker and promising target for patients with breast cancer.


Assuntos
Neoplasias da Mama , Proteínas F-Box , Feminino , Humanos , Biomarcadores , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Prognóstico
10.
J Cancer Res Clin Oncol ; 149(10): 6967-6977, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36849756

RESUMO

PURPOSE: To explore transcriptome and immunological features of patients with Ewing sarcoma (ES) using all publicly available microarray data. METHODS: Data of 479 ES tissues were integrated and normalized. Gene expression, immune infiltration, and cancer-specific pathways were analyzed. Genes of interest were knocked down, followed by cell proliferation and colony formation assays. RESULTS: Consistent with the previous reports of differential expressed genes (DEGs) in ES, our analysis identified CCND1, HMCN1, and NKX2-2 were among the most highly expressed, while TWNC1, MYBPC1, and CKM were among the lowest expressed genes. GO, KEGG, and GSEA enrichment analysis identified that the DEGs related to bone and muscle functioning, those that contributed to crucial cellular, and metabolism pathways such as actin binding, apoptosis, TCA cycle, and cell cycle were also significantly enriched. Immune infiltration analysis discovered that many T cell subsets including CD4T, CD8 T, and Gamma delta T cells were highly infiltrated, while monocytes and B cells were less infiltrated in tumors. A total of 138 genes were both significantly up-regulated in tumors and associated with decreased survival, while 38 significantly down-regulated genes were associated with increased survival, many of which were previously reported as oncogenes and tumor suppressors in ES and other cancers. Silencing of four newly identified top ranked up-regulated genes with decreased survivals in ES inhibited proliferation and colony formation of ES cells. CONCLUSION: This study may provide a clear representative transcriptome profile of ES, providing diagnostic biomarkers, pathways, and immune infiltrative characteristics targets for ES.


Assuntos
Sarcoma de Ewing , Humanos , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Transcriptoma , Proliferação de Células/genética , Apoptose/genética
11.
Mol Genet Genomics ; 298(3): 521-535, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36813858

RESUMO

MicroRNAs (miRNAs), important regulators of gene expression, play critical roles in various biological processes and tumorigenesis. To reveal the potential relationships between multiple isomiRs and arm switching, we performed a comprehensive pan-cancer analysis to discuss their roles in tumorigenesis and cancer prognosis. Our results showed that many miR-#-5p and miR-#-3p pairs from the two arms of pre-miRNA may have abundant expression levels, and they are often involved in distinct functional regulatory networks by targeting different mRNAs, although they may also interact with common targets. The two arms may show diverse isomiR expression landscapes, and their expression ratio might vary, mainly depending on tissue type. Dominantly expressed isomiRs can be used to determine distinct cancer subtypes that are associated with clinical outcome, indicating that they may be potential prognostic biomarkers. Our findings indicate robust and flexible isomiR expression landscapes that will enrich the study of miRNAs/isomiRs and aid in revealing the potential roles of multiple isomiRs yielded by arm switching in tumorigenesis.


Assuntos
MicroRNAs , Neoplasias , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/genética , Carcinogênese/genética
12.
Mol Biomed ; 3(1): 28, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36109447

RESUMO

Periodontitis is one of the most prevalent chronic inflammatory diseases and Polyphenols isolated from Turkish gall play a major role in the treatment of inflammatory diseases for their antibacterial, anti-inflammatory and antioxidant activities. In this work, Turkish Galls effective constituent (TGEC, T) was prepared into nanoparticles (T-NPs) by principle of oxidative self-polymerization. The pH-sensitive T-NPs was encapsulated into thermosensitive type in-situ hydrogel, and 42.29 ± 1.12% of effective constituent from T-NPs were continuously released within 96 h under the periodontitis environment. In addition, the weakly alkaline oral micro-environment of patients with periodontitis is more conducive to the sustained release of effective constituent, which is 10.83% more than that of healthy periodontal environment. The bacteriostatic test showed that T-NPs had stronger antibacterial activity on oral pathogens than that of TGEC. Compared with TGEC, the minimum inhibitory concentration (MIC) of T-NPs against P. gingivalis and A. viscosus was reduced by 50% and 25%, respectively. Interestingly, T-NPs induced bacteria lysis by promoting the excessive production of ROS without periodontal tissue damage caused by excessive oxidation reaction. In conclusion, a simple method of preparing microspheres with natural polyphenols was developed, which provides beneficial reference for one-step prepared drug carriers from effective components of natural product, likewise the method offers a green and effective solution to synthesis a new adjuvant therapy drugs for treatment of gingivitis associated with periodontal pockets.

13.
Exp Hematol Oncol ; 10(1): 54, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34798909

RESUMO

Hepatocellular carcinoma (HCC) is a common malignancy in human. CD44 is a transmembrane glycoprotein which is frequently overexpressed in cancer of various origins. The function and mechanism of CD44 in HCC remains elusive. In this study, we reported that CD44 was overexpressed in HCC to promote the proliferation and migration of HCC cells via oncogenic YAP, which is the key downstream regulator in Hippo pathway. These findings suggest that CD44-YAP is a probable important axis in pathogenesis of HCC, providing an insight in to HCC pathogenesis as well as potential targets for the intervention of HCC.

14.
Analyst ; 146(16): 5135-5142, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34282821

RESUMO

Nitrogen doped carbon dots were synthesized using the hydrothermal reaction of cellulose and urea, and then carbonized in a N2 atmosphere at a high temperature to prepare N-doped carbon dots decorated with manganese oxide nanospheres (N-CMOS) formed using cetyltrimethylammonium bromide (CTAB) and MnO. The introduction of N-CMOS resulted in a large specific surface area, abundant pores, favourable conductivity and an excellent electrocatalytic performance. A glassy carbon electrode modified with N-CMOS was used for the simultaneous identification of paracetamol (AP) and p-aminophenol (PAP) utilising differential pulse voltammetry. Under optimum conditions, the electrical sensor showed a wide linear range of 0.1-100 µM for PAP and 0.1-80 µM for AP, with detection limits of 0.0456 and 0.0303 µM (S/N = 3), respectively. The sensitivities for detecting PAP and AP were calculated as 1.615 and 1.971 µA µM-1 cm-2, respectively. The sensitivity and limit of detection (LOD) meet the requirements of detection of drug impurity limits in tablets. In addition, the sensor has been successfully applied to detect PAP and AP in paracetamol tablets. The constructed sensor not only possesses a superior repeatability, reproducibility and stability, but a relatively wide linear range, and a superior detection limit and sensitivity.


Assuntos
Carbono , Nanosferas , Acetaminofen , Aminofenóis , Técnicas Eletroquímicas , Eletrodos , Limite de Detecção , Compostos de Manganês , Óxidos , Reprodutibilidade dos Testes
15.
Cell Death Dis ; 12(3): 251, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674562

RESUMO

Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug approved to treat multiple myeloma and mantle cell lymphoma, as BTZ exhibits toxic effects on diverse tumor cells. Herein, we show that CPX displays strong anti-tumorigenic activity on GBM. Mechanistically, CPX inhibits GBM cellular migration and invasion by reducing N-Cadherin, MMP9 and Snail expression. Further analysis revealed that CPX suppresses the expression of several key subunits of mitochondrial enzyme complex, thus leading to the disruption of mitochondrial oxidative phosphorylation (OXPHOS) in GBM cells. In combination with BTZ, CPX promotes apoptosis in GBM cells through the induction of reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling. Moreover, CPX and BTZ synergistically activates nuclear factor kappa B (NF-κB) signaling and induces cellular senescence. Our findings suggest that a combination of CPX and BTZ may serve as a novel therapeutic strategy to enhance the anticancer activity of CPX against GBM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bortezomib/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Ciclopirox/farmacologia , Glioblastoma/tratamento farmacológico , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Fosforilação Oxidativa/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Mikrochim Acta ; 187(7): 395, 2020 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-32564229

RESUMO

Three-dimensional porous gold nanoparticles (NPG) were synthesized in situ on indium-doped tin oxide (ITO) substrates by a green and convenient one-step electrodeposition method to achieve super-sensitive As(III) detection. The introduction of NPG method not only greatly improves the electron transfer capacity and surface area of sensor interface but provides more active sites for As(III) enrichment, thus boosting sensitivity and selectivity. The sensor was characterized by scanning electron microscopy, energy dispersion spectroscopy, differential pulse anode stripping voltammetry (DPASV), and electrochemical impedance to evaluate its morphology, composition, and electrochemical performance. The wall thickness of NPG was customized by optimizing the concentration of electroplating solution, dissolved electrolyte, deposition potential, and reaction time. Under optimal conditions, the electrochemical sensor showed a wide linear range from 0.1 to 50 µg/L As(III), with a detection limit (LOD) of 0.054 µg/L (S/N = 3). The LOD is far below 10 µg/L, the recommended maximum value by the world health organization for drinking water. Stability, reproducibility, and repeatability of NGP/ITO were determined to be 2.77%, 4.9%, and 4.1%, respectively. Additionally, the constructed sensor has been successfully applied to determine As(III) in three actual samples, and the results are in good agreement with that of hydride generation atomic fluorescence spectrometry (AFS). Graphical abstract.

17.
J Cell Mol Med ; 24(3): 2135-2144, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31944568

RESUMO

Breast cancer is the second leading death cause of cancer death for all women. Previous study suggested that Protein Kinase D3 (PRKD3) was involved in breast cancer progression. In addition, the protein level of PRKD3 in triple-negative breast adenocarcinoma was higher than that in normal breast tissue. However, the oncogenic mechanisms of PRKD3 in breast cancer is not fully investigated. Multi-omic data showed that ERK1/c-MYC axis was identified as a major pivot in PRKD3-mediated downstream pathways. Our study provided the evidence to support that the PRKD3/ERK1/c-MYC pathway play an important role in breast cancer progression. We found that knocking out PRKD3 by performing CRISPR/Cas9 genome engineering technology suppressed phosphorylation of both ERK1 and c-MYC but did not down-regulate ERK1/2 expression or phosphorylation of ERK2. The inhibition of ERK1 and c-MYC phosphorylation further led to the lower protein level of c-MYC and then reduced the expression of the c-MYC target genes in breast cancer cells. We also found that loss of PRKD3 reduced the rate of the cell proliferation in vitro and tumour growth in vivo, whereas ectopic (over)expression of PRKD3, ERK1 or c-MYC in the PRKD3-knockout breast cells reverse the suppression of the cell proliferation and tumour growth. Collectively, our data strongly suggested that PRKD3 likely promote the cell proliferation in the breast cancer cells by activating ERK1-c-MYC axis.


Assuntos
Neoplasias da Mama/genética , Proliferação de Células/genética , Proteína Quinase Ativada por DNA/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Oncogenes/genética , Fosforilação/genética , Transdução de Sinais/genética
18.
Cell Oncol (Dordr) ; 43(1): 65-80, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31701491

RESUMO

PURPOSE: Endocrine therapy is the most commonly used approach for the treatment of estrogen receptor (ERα)-positive breast cancer. The cure rate of patients with ERα-positive breast cancer is, however, limited due to the occurrence of endocrine resistance. Loss of ERα is one major mechanism for the occurrence of endocrine resistance. Recent studies have shown that pan-HDAC inhibitors may be effective in reversing endocrine resistance. However, the molecular mechanism underlying this reversal has remained largely unknown. Here we aimed to unravel this mechanism. METHODS: Endocrine resistant breast cancer cell lines were established through exposure to tamoxifen. mRNA expression was assessed by qRT-PCR and protein expression by Western blotting. The effect of HDAC3 inhibition on the viability of endocrine resistant breast cancer cells was evaluated using CCK-8 and colony forming assays. Immunohistochemistry was used to detect protein expression in primary breast cancer tissues. RESULTS: We found that in endocrine resistant breast cancer cells loss of ERα led to HDAC3 stabilization via decreased ERα-mediated caspase7 expression, resulting in reduced caspase7-mediated HDAC3 cleavage. We also found that the ERα-caspase7-HDAC3 axis determined the global H3K9 and H4K16 acetylation status, which was positively correlated with ERα expression. Finally, we found that inhibition of HDAC3 significantly decreased the viability of endocrine resistant breast cancer cells exhibiting ERα deficiency. The ERα-caspase7-HDAC3 axis was subsequently verified in primary endocrine resistant breast cancer samples. CONCLUSIONS: From our data we conclude that the ERα-caspase7-HDAC3 axis may play a role in promoting the proliferation of endocrine resistant breast cancer cells. HDAC3 may serve as a therapeutic target for (a subset of) endocrine resistant breast cancers exhibiting ERα loss.


Assuntos
Neoplasias da Mama/metabolismo , Caspase 7/metabolismo , Proliferação de Células , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/metabolismo , Histona Desacetilases/metabolismo , Acetilação , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Caspase 7/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Humanos , Imuno-Histoquímica , Interferência de RNA , Tamoxifeno/farmacologia
19.
Aging (Albany NY) ; 11(24): 12295-12314, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31848326

RESUMO

The mitogen-activated protein kinase/extracellular signal-regulated (MAPK/ERK) pathway is a well-characterized signaling pathway during the development of various cancer types. ERK1 and ERK2, the two kinase effectors of MAPK cascade, exhibit high similarity. However, it is still unknown whether these two kinases are functionally different or in contrast functionally redundant during the development of breast cancer. We found that ERK1 expression levels were significantly lower in basal breast cancer compared with luminal breast cancer and normal breast tissues. RNA sequencing data suggested that ERK1 was associated with Hippo signaling pathway and cell proliferation in breast cancer cells. The gene set enrichment analysis (GSEA) further showed enrichment for YAP1 signaling pathway in breast cancer cell lines and tumors with low expression of ERK1. Silencing of ERK1 elevated YAP1 expression and TEAD activity in breast cancer cells. Additionally, ERK1 inhibited breast cancer cell proliferation via regulation of YAP1. The Kaplan-Meier analysis of data in patients with breast cancer suggested that, higher expression of ERK1 was associated with better prognosis, whereas, higher expression of ERK2 predicted poorer prognosis. These findings unveiled the role of ERK1 on regulation of YAP1 signaling pathway, indicating ERK1 as a negative regulator of breast cancer progression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Neoplasias da Mama , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , Proteína Quinase 3 Ativada por Mitógeno/genética , Neoplasias Experimentais , Prognóstico , Transdução de Sinais , Fatores de Transcrição/genética , Proteínas de Sinalização YAP
20.
Cell Physiol Biochem ; 52(3): 382-396, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30845378

RESUMO

BACKGROUND/AIMS: Breast cancer is clinically classified into three main subtypes: estrogen receptor-positive (ER+) breast cancer, human epidermal growth factor receptor 2-positive (HER2+) breast cancer, and triple-negative breast cancer (TNBC). Without specific targeted therapies, patients with TNBC have poorer prognosis compared with those with ER+ and HER2+ breast cancer. Protein kinase D (PRKD) family members play crucial roles in cancer progression. CRT0066101, a PRKD inhibitor, has been reported to have anticancer activity in many cancer types. Nevertheless, the role and mechanism of CRT0066101 in TNBC have not been well investigated. METHODS: The expression level of PRKDs was analyzed in breast cancer samples and breast cancer cell lines. The effects of inhibiting PRKD activity with CRT0066101 on TNBC cell proliferation, cell cycle, apoptosis, and tumor growth were studied by Cell Counting Kit8 assay, cell cycle assay, propidium iodide/annexin-V assay, and a xenograft mouse model, respectively. To uncover the molecular mechanism of CRT0066101 in TNBC, comparative phosphoproteomic analysis using iTRAQ was employed. RESULTS: We found that PRKD2 and PRKD3 were preferentially expressed in breast cancers. Immunohistochemistry confirmed the overexpression of PRKD2 and PRKD3 in TNBC. CRT0066101, which inhibited the activity of PRKDs, dramatically inhibited proliferation, increased apoptosis and the G1-phase population of TNBC cells in vitro, and reduced breast tumor volume in vivo. Comparative phosphoproteomic analysis between breast cancer cells with and without CRT0066101 treatment revealed that the anti-breast cancer effects involved regulation of a complex network containing multiple enriched pathways and several hub-nodes contributing to multiple cancer-related processes, thus explaining the described effects of CRT0066101 on TNBC in vitro and in vivo. Finally, we validated several targets of PRKD inhibition by treatment with CRT0066101 and small interfering RNAs against PRKD2 and PRKD3 (siPRKD2 and siPRKD3), including p-MYC(T58/ S62), p-MAPK1/3(T202/Y204), p-AKT(S473), p-YAP(S127), and p-CDC2(T14). CONCLUSION: PRKD inhibitor CRT0066101 exhibits anti-TNBC effects via modulating a phosphor-signaling network and inhibiting the phosphorylation of many cancer-driving factors, including MYC, MAPK1/3, AKT, YAP, and CDC2, providing insight into the important roles as well as the molecular mechanism of CRT0066101 as an effective drug for TNBC.


Assuntos
Apoptose/efeitos dos fármacos , Pirimidinas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Fosfopeptídeos/análise , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Proteômica , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
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