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1.
Sci Rep ; 14(1): 15406, 2024 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965397

RESUMO

Patients with multiple myeloma (MM) experience relapse and drug resistance; therefore, novel treatments are essential. Clotrimazole (CTZ) is a wide-spectrum antifungal drug with antitumor activity. However, CTZ's effects on MM are unclear. We investigated CTZ's effect on MM cell proliferation and apoptosis induction mechanisms. CTZ's effects on MM.1S, NCI- H929, KMS-11, and U266 cell growth were investigated using Cell Counting Kit-8 (CCK-8) assay. The apoptotic cell percentage was quantified with annexin V-fluorescein isothiocyanate/7-amino actinomycin D staining. Mitochondrial membrane potential (MMP) and cell cycle progression were evaluated. Reactive oxygen species (ROS) levels were measured via fluorescence microscopy. Expression of apoptosis-related and nuclear factor (NF)-κB signaling proteins was analyzed using western blotting. The CCK-8 assay indicated that CTZ inhibited cell proliferation based on both dose and exposure time. Flow cytometry revealed that CTZ decreased apoptosis and MMP and induced G0/G1 arrest. Immunofluorescence demonstrated that CTZ dose-dependently elevated in both total and mitochondrial ROS production. Western blotting showed that CTZ enhanced Bax and cleaved poly ADP-ribose polymerase and caspase-3 while decreasing Bcl-2, p-p65, and p-IκBα. Therefore, CTZ inhibits MM cell proliferation by promoting ROS-mediated mitochondrial apoptosis, inducing G0/G1 arrest, inhibiting the NF-κB pathway, and has the potential for treating MM.


Assuntos
Apoptose , Proliferação de Células , Clotrimazol , Potencial da Membrana Mitocondrial , Mitocôndrias , Mieloma Múltiplo , Espécies Reativas de Oxigênio , Humanos , Mieloma Múltiplo/patologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Clotrimazol/farmacologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
2.
Molecules ; 29(7)2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38611789

RESUMO

Natural chemicals derived from herbal plants have recently been recognized as potentially useful treatment alternatives owing to their ability to target a wide range of important biological molecules. Cynaroside is one of these natural compounds with promising anticancer activity for numerous tumor types. Nevertheless, the anticancer effects and molecular mechanisms of action of cynaroside on colorectal cancer (CRC) remain unclear. In this study, cynaroside was found to markedly inhibit CRC cell proliferation and colony formation in vitro. Cynaroside also inhibited cell proliferation in vivo and decreased the expression of KI67, a cell nuclear antigen. RNA sequencing revealed 144 differentially expressed genes (DEGs) in HCT116 cells and 493 DEGs in RKO cells that were enriched in the cell cycle signaling pathway. Cell division cycle 25A (CDC25A), a DEG widely enriched in the cell cycle signaling pathway, is considered a key target of cynaroside in CRC cells. Cynaroside also inhibited DNA replication and arrested cells in the G1/S phase in vitro. The expression levels of CDC25A and related G1-phase proteins were significantly elevated after CDC25A overexpression in CRC cells, which partially reversed the inhibitory effect of cynaroside on CRC cell proliferation and G1/S-phase arrest. In summary, cynaroside may be used to treat CRC as it inhibits CDC25A expression.


Assuntos
Neoplasias Colorretais , Glucosídeos , Humanos , Pontos de Checagem da Fase G1 do Ciclo Celular , Luteolina , Neoplasias Colorretais/tratamento farmacológico
3.
Med Oncol ; 41(5): 105, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38573558

RESUMO

Human laryngeal squamous carcinoma (LSCC) is a common malignant tumor in the head and neck. Despite the recently developed therapies for the treatment of LSCC, patients' overall survival rate still did not enhance remarkably; this highlights the need to formulate alternative strategies to develop novel treatments. The antitumor effects of antidepressant drugs such as citalopram have been reported on several cancer cells; however, they have yet to be investigated against LSCC. The current study was directed to explore the possible antitumor effects of citalopram on human laryngeal carcinoma cell lines (HEP-2). HEP-2 cells were cultured and treated with different doses of citalopram (50-400 µM) for 24, 48, and 72 h. The effects of citalopram on the viability of cancer cells were determined by the MTT assay. In addition, apoptosis and cell cycle analysis were performed by flow cytometry. Moreover, evaluation of the expression of proapoptotic and apoptotic proteins, such as cytochrome c, cleaved caspases 3 and 9, Bcl-2, and BAX, was performed by western blotting analysis. Our results revealed that citalopram significantly suppressed the proliferation of HEP-2 cells through the upregulation of p21 expression, resulting in the subsequent arrest of the cell cycle at the G0/G1 phase. Furthermore, citalopram treatment-induced HEP-2 cell apoptosis; this was indicated by the significant increase of cytochrome c, cleaved caspases 3 and 9, and BAX protein expression. On the contrary, Bcl-2 protein expression was significantly downregulated following treatment with citalopram. The ultrastructure studies were in accordance with the protein expression findings and showed clear signs of apoptosis with ring chromatin condensation upon treatment with citalopram. These findings suggest that citalopram's anti-tumor activities on HEP-2 cells entailed stimulation of the intrinsic apoptotic pathway, which was mediated via Bcl-2 suppression.


Assuntos
Antipsicóticos , Carcinoma , Humanos , Citalopram/farmacologia , Fase de Repouso do Ciclo Celular , Citocromos c , Apoptose , Pontos de Checagem da Fase G1 do Ciclo Celular , Proteínas Proto-Oncogênicas c-bcl-2
4.
Cell Commun Signal ; 22(1): 158, 2024 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-38439036

RESUMO

BACKGROUND: BMP9 and BMP10 are two major regulators of vascular homeostasis. These two ligands bind with high affinity to the endothelial type I kinase receptor ALK1, together with a type II receptor, leading to the direct phosphorylation of the SMAD transcription factors. Apart from this canonical pathway, little is known. Interestingly, mutations in this signaling pathway have been identified in two rare cardiovascular diseases, hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension. METHODS: To get an overview of the signaling pathways modulated by BMP9 and BMP10 stimulation in endothelial cells, we employed an unbiased phosphoproteomic-based strategy. Identified phosphosites were validated by western blot analysis and regulated targets by RT-qPCR. Cell cycle analysis was analyzed by flow cytometry. RESULTS: Large-scale phosphoproteomics revealed that BMP9 and BMP10 treatment induced a very similar phosphoproteomic profile. These BMPs activated a non-canonical transcriptional SMAD-dependent MAPK pathway (MEKK4/P38). We were able to validate this signaling pathway and demonstrated that this activation required the expression of the protein GADD45ß. In turn, activated P38 phosphorylated the heat shock protein HSP27 and the endocytosis protein Eps15 (EGF receptor pathway substrate), and regulated the expression of specific genes (E-selectin, hyaluronan synthase 2 and cyclooxygenase 2). This study also highlighted the modulation in phosphorylation of proteins involved in transcriptional regulation (phosphorylation of the endothelial transcription factor ERG) and cell cycle inhibition (CDK4/6 pathway). Accordingly, we found that BMP10 induced a G1 cell cycle arrest and inhibited the mRNA expression of E2F2, cyclinD1 and cyclinA1. CONCLUSIONS: Overall, our phosphoproteomic screen identified numerous proteins whose phosphorylation state is impacted by BMP9 and BMP10 treatment, paving the way for a better understanding of the molecular mechanisms regulated by BMP signaling in vascular diseases.


Assuntos
Proteínas Morfogenéticas Ósseas , Células Endoteliais , Pontos de Checagem do Ciclo Celular , Fosforilação , Pontos de Checagem da Fase G1 do Ciclo Celular
5.
Biochim Biophys Acta Gen Subj ; 1868(6): 130600, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38508285

RESUMO

OBJECTIVES: Lung cancer is a leading cause of cancer-related mortality and remains one of the most poorly prognosed disease worldwide. Therefore, it is necessary to identify novel molecular markers with potential therapeutic effects. Recent findings have suggested that dual-specificity tyrosine-regulated kinase 2 (DYRK2) plays a tumor suppressive role in colorectal, breast, and hepatic cancers; however, its effect and mechanism in lung cancer remain poorly understood. Therefore, this study aimed to investigate the tumor-suppressive role and molecular mechanism of DYRK2 in lung adenocarcinoma (LUAD) by in vitro experiments and xenograft models. MATERIALS AND METHODS: The evaluation of DYRK2 expression was carried out using lung cancer cell lines and normal bronchial epithelial cells. Overexpression of DYRK2 was induced by an adenovirus vector, and cell proliferation was assessed through MTS assay and Colony Formation Assay. Cell cycle analysis was performed using flow cytometry. Additionally, proliferative capacity was evaluated in a xenograft model by subcutaneously implanting A549 cells into SCID mice (C·B17/Icr-scidjcl-scid/scid). RESULTS: Immunoblotting assays showed that DYRK2 was downregulated in most LUAD cell lines. DYRK2 overexpression using adenovirus vectors significantly suppressed cell proliferation compared with that in the control group. Additionally, DYRK2 overexpression suppressed tumor growth in a murine subcutaneous xenograft model. Mechanistically, DYRK2 overexpression inhibited the proliferation of LUAD cells via p21-mediated G1 arrest, which was contingent on p53. CONCLUSION: Taken together, these findings suggest that DYRK2 may serve as potential prognostic biomarker and therapeutic target for LUAD.


Assuntos
Adenocarcinoma de Pulmão , Proliferação de Células , Quinases Dyrk , Pontos de Checagem da Fase G1 do Ciclo Celular , Neoplasias Pulmonares , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Animais , Humanos , Camundongos , Células A549 , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/genética , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Camundongos SCID , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Molecules ; 29(3)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38338430

RESUMO

(1) Background: Colorectal cancer (CRC) is the third most common malignant tumor worldwide and the second most common cause of cancer death. However, effective anti-CRC drugs are still lacking in clinical settings. This article investigated the anti-proliferative effect of involucrasin B on CRC Caco-2 cells. (2) Methods: This study employed a sulforhodamine B (SRB) method, colony formation experiments, flow cytometry, FastFUCCI assay, dual luciferase assay, and Western blot analysis for the investigation. (3) Results: The SRB method and colony formation experiments showed that involucrasin B exhibited an inhibitory effect on the Caco-2 cells cultured in vitro. Subsequently, the flow cytometry, FastFUCCI assay, and Western blotting results showed that involucrasin B induced cell cycle arrest in the G1 phase dose-dependently. Involucrasin B significantly enhanced the TGFß RII protein level and SMAD3 phosphorylation, thus inhibiting the expression of CDK4 and cyclin D1 and causing G1 cell cycle arrest. (4) Conclusion: This study shows that involucrasin B exerts its anti-proliferative effect by regulating the TGFß/SMAD2-3-4 pathway to cause G1 cycle arrest in Caco-2 cells.


Assuntos
Fator de Crescimento Transformador beta , Humanos , Células CACO-2 , Fosforilação , Pontos de Checagem da Fase G1 do Ciclo Celular , Proliferação de Células , Fator de Crescimento Transformador beta/farmacologia , Linhagem Celular Tumoral , Proteína Smad2
7.
Cancer Chemother Pharmacol ; 93(5): 411-425, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38191768

RESUMO

BACKGROUND: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies. METHODS: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties. RESULTS: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1ß, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.


Assuntos
Apoptose , Artemisininas , Neoplasias do Colo , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Artemisininas/farmacologia , Artemisininas/química , Apoptose/efeitos dos fármacos , Neoplasias do Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Imunidade Adaptativa/efeitos dos fármacos , Rutênio/química , Rutênio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Células HCT116 , Células HT29 , Animais , Citocinas/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Camundongos
8.
Mol Carcinog ; 63(4): 647-662, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38197491

RESUMO

Colorectal cancer (CRC) continues to be a prevalent malignancy, posing a significant risk to human health. The involvement of alpha/beta hydrolase domain 6 (ABHD6), a serine hydrolase family member, in CRC development was suggested by our analysis of clinical data. However, the role of ABHD6 in CRC remains unclear. This study seeks to elucidate the clinical relevance, biological function, and potential molecular mechanisms of ABHD6 in CRC. We investigated the role of ABHD6 in clinical settings, conducting proliferation, migration, and cell cycle assays. To determine the influence of ABHD6 expression levels on Oxaliplatin sensitivity, we also performed apoptosis assays. RNA sequencing and KEGG analysis were utilized to uncover the potential molecular mechanisms of ABHD6. Furthermore, we validated its expression levels using Western blot and reactive oxygen species (ROS) detection assays. Our results demonstrated that ABHD6 expression in CRC tissues was notably lower compared to adjacent normal tissues. This low expression correlated with a poorer prognosis for CRC patients. Moreover, ABHD6 overexpression impeded CRC cell proliferation and migration while inducing G0/G1 cell cycle arrest. In vivo experiments revealed that downregulation of ABHD6 resulted in an increase in tumor weight and volume. Mechanistically, ABHD6 overexpression inhibited the activation of the AKT signaling pathway and decreased ROS levels in CRC cells, suggesting the role of ABHD6 in CRC progression via the AKT signaling pathway. Our findings demonstrate that ABHD6 functions as a tumor suppressor, primarily by inhibiting the AKT signaling pathway. This role establishes ABHD6 as a promising prognostic biomarker and a potential therapeutic target for CRC patients.


Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas c-akt , Humanos , Espécies Reativas de Oxigênio , Proliferação de Células , Pontos de Checagem da Fase G1 do Ciclo Celular , Hidrolases , Transdução de Sinais , Neoplasias Colorretais/genética , Linhagem Celular Tumoral , Movimento Celular , Monoacilglicerol Lipases
9.
Biochem Pharmacol ; 221: 116038, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38286211

RESUMO

PERK/eIF2α/ATF4/CHOP signaling pathway is one of three major branches of unfolded protein response (UPR) and has been implicated in tumor progression. CCT020312 is a selective PERK activator and may have a potential anti-tumor effect. Here we investigated the anti-prostate cancer effect and its underlying mechanism of CCT020312. Our results showed that CCT020312 inhibited prostate cancer cell viability by inducing cell cycle arrest, apoptosis and autophagy through activation of PERK/eIF2α/ATF4/CHOP signaling. CCT020312 treatment caused cell cycle arrest at G1 phase and increased the levels of cleaved-Caspase3, cleaved-PARP and Bax in prostate cancer C4-2 and LNCaP cells. Moreover, CCT020312 increased LC3II/I, Atg12-Atg5 and Beclin1 levels and induced autophagosome formation. Furthermore, knockdown of CHOP reversed CCT020312-induced cell viability decrease, apoptosis and autophagy. Bafilomycin A1 reversed CCT020312-induced cell viability decrease but had no effect on CCT020312-induced CHOP activation in C4-2 and LNCaP cells. In vivo, CCT020312 suppressed tumor growth in C4-2 cells-derived xenograft mouse model, activated PERK pathway, and induced autophagy and apoptosis. Our study illustrates that CCT020312 exerts an anti-tumor effect in prostate cancer via activating the PERK pathway, thus indicating that CCT020312 may be a potential drug for prostate cancer.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Animais , Camundongos , Pontos de Checagem da Fase G1 do Ciclo Celular , Neoplasias da Próstata/tratamento farmacológico , Autofagia , Apoptose , Transdução de Sinais , Modelos Animais de Doenças , Fator 4 Ativador da Transcrição/genética
10.
J Sci Food Agric ; 104(3): 1741-1755, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37862230

RESUMO

BACKGROUND: Porcupine quills, a by-product of porcupine pork, are rich in keratin, which is an excellent source of bioactive peptides. The objective of this study was to investigate the underlying mechanism of anti-proliferation effect of porcupine quills keratin peptides (PQKPs) on MCF-7 cells. RESULTS: Results showed that PQKPs induced MCF-7 cells apoptosis by significantly decreasing the secretion level of anti-apoptosis protein Bcl-2 and increasing the secretion levels of pro-apoptosis proteins Bax, cytochrome c, caspase 9, caspase 3 and PARP. PQKPs also arrested the cell cycle at G0/G1 phase via remarkably reducing the protein levels of CDK4 and enhancing the protein levels of p53 and p21. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis identified nine peptides with molecular weights less than 1000 Da in PQKPs. Molecular docking results showed that TPGPPT and KGPAC identified from PQKPs could bind with p53 mutant and Bcl-2 protein by conventional hydrogen bonds, carbon hydrogen bonds and van der Waals force. Furthermore, the anti-proliferation impact of synthesized peptides (TPGPPT and KGPAC) was shown in MCF-7 cells. CONCLUSION: These findings indicated that PQKPs suppressed the proliferation of MCF-7 breast cancer cells by triggering apoptosis and G0/G1 cell cycle arrest. Moreover, the outcome of this study will bring fresh insights into the production and application of animal byproducts. © 2023 Society of Chemical Industry.


Assuntos
Neoplasias da Mama , Porcos-Espinhos , Humanos , Animais , Feminino , Células MCF-7 , Caspases/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Porcos-Espinhos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Queratinas/metabolismo , Simulação de Acoplamento Molecular , Espectrometria de Massas em Tandem , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/farmacologia , Ciclo Celular , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células , Linhagem Celular Tumoral
11.
Mol Cell ; 83(22): 4047-4061.e6, 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37977117

RESUMO

CDK4/6 inhibitors are remarkable anti-cancer drugs that can arrest tumor cells in G1 and induce their senescence while causing only relatively mild toxicities in healthy tissues. How they achieve this mechanistically is unclear. We show here that tumor cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing progression from G1 or inducing genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage, and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize the cells to CDK4/6 inhibition. Together, this demonstrates that cell cycle arrest and oncogenic cell growth is a synthetic lethal combination that is exploited by CDK4/6 inhibitors to induce tumor-specific toxicity.


Assuntos
Antineoplásicos , Neoplasias , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Proteína Supressora de Tumor p53/genética , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética
12.
Med Oncol ; 40(8): 215, 2023 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-37382687

RESUMO

Focal adhesion kinase (FAK) is a promising therapeutic target for various cancers and its inhibitor development is in full swing. PF-562271 is a classic FAK inhibitor that has shown promising preclinical data and has been found to exhibit an anti-migration effect on some cancer cells. However, its anticancer effect on high-grade serous ovarian cancer (HGSOC) has not been reported. In this study, we evaluated the anti-migration and anti-proliferation effects of PF-562271 against HGSOC SKOV3 and A2780 cells, as well as the underlying mechanism. The results demonstrated that FAK was overexpressed in clinical HGSOC tissues and was positively correlated with the pathological progression of HGSOC. Moreover, HGSOC patients with high FAK expression levels exhibited low survival rates. PF-562271 treatment significantly inhibited the cell adhesion and migration of SKOV3 and A2780 cells by inhibiting p-FAK expression and decreasing the FA surface area. Additionally, PF-562271 treatment inhibited colony formation and induced cell senescence through G1 phase cell cycle arrest mediated DNA replication inhibition. Taken together, the findings demonstrated that FAK inhibitor PF-562271 significantly inhibits HGSOC cell adhesion, migration, and proliferation process through FAK and/or FAK mediated cell cycle arrest, and suggested that PF-562271 could serve as a potential oncotherapeutic agent for HGSOC targeting treatment.


Assuntos
Neoplasias Ovarianas , Feminino , Humanos , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proteína-Tirosina Quinases de Adesão Focal , Pontos de Checagem da Fase G1 do Ciclo Celular , Neoplasias Ovarianas/tratamento farmacológico
13.
Acta Biochim Pol ; 70(2): 271-276, 2023 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-37307139

RESUMO

Oral cancer is one of the commonly reported malignancies of the human oral cavity and pharynx. It accounts for a significant level of cancer-based mortality across the globe. Long non-coding RNAs (lncRNAs) are emerging as important study targets in cancer therapy. The present study aimed to characterize the role of lncRNA GASL1 in regulating the growth, migration, and invasion of human oral cancer cells. The qRT-PCR showed significant (P<0.05) upregulation of GASL1 in oral cancer cells. Overexpression of GASL1 led to the loss of viability of HN6 oral cancer cells by inducing apoptosis which was associated with upregulation of Bax and downregulation of Bcl-2. The apoptotic cell percentage increased from 2. 81% in control to 25.89% upon GASL1 overexpression. Cell cycle analysis showed that overexpression of GASL1 increased the G1 cells from 35.19% in control to 84.52% upon GASL1 overexpression indicative of G0/G1 cell cycle arrest. Cell cycle arrest was also accompanied by inhibition of cyclin D1 and CDK4 protein expression. Wound healing and transwell assays showed that overexpression of GASL1 significantly (P<0.05) inhibited the migration and invasion of HN6 oral cancer cells. The invasion of the HN6 oral cancer cells was found to be decreased by more than 70%. Finally, the results of in vivo study revealed that GASL1 overexpression inhibits the xenografted tumor growth in vivo. Thus, the results are thus suggestive of the tumor-suppressive molecular role of GASL1 in oral cancer cells.


Assuntos
Neoplasias Bucais , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Proliferação de Células/genética , Linhagem Celular Tumoral , Apoptose/genética , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Ciclo Celular/genética
14.
Int J Mol Sci ; 24(12)2023 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-37373067

RESUMO

Prohibitin (PHB) is a tumour suppressor gene with several different molecular activities. PHB overexpression leads to G1/S-phase cell cycle arrest, and PHB represses the androgen receptor (AR) in prostate cancer cells. PHB interacts with and represses members of the E2F family in a manner that may also be AR-linked, therefore making the AR:PHB:E2F interaction axis highly complex. PHB siRNA increased the growth and metastatic potential of LNCaP mouse xenografts in vivo. Conversely, PHB ectopic cDNA overexpression affected several hundred genes in LNCaP cells. Furthermore, gene ontology analysis showed that in addition to cell cycle regulation, several members of the WNT family were significantly downregulated (WNT7B, WNT9A and WNT10B), as well as pathways for cell adhesion. Online GEO data studies showed PHB expression to be decreased in clinical cases of metastatic prostate cancer, and to be correlated with higher WNT expression in metastasis. PHB overexpression reduced prostate cancer cell migration and motility in wound-healing assays, reduced cell invasion through a Matrigel layer and reduced cellular attachment. In LNCaP cells, WNT7B, WNT9A and WNT10B expression were also upregulated by androgen treatment and downregulated by androgen antagonism, indicating a role for AR in the control of these WNT genes. However, these WNTs were strongly cell cycle regulated. E2F1 cDNA ectopic expression and PHB siRNA (both cell cycle promoting effects) increased WNT7B, WNT9A and WNT10B expression, and these genes were also upregulated as cells were released from G1 to S phase synchronisation, indicating further cell cycle regulation. Therefore, the repressive effects of PHB may inhibit AR, E2F and WNT expression and its loss may increase metastatic potential in human prostate cancer.


Assuntos
Androgênios , Proibitinas , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Androgênios/farmacologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , DNA Complementar , Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Proibitinas/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , RNA Interferente Pequeno/farmacologia
15.
Cell Mol Biol (Noisy-le-grand) ; 69(2): 12-18, 2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-37224052

RESUMO

Hepatic cancer was the third most prevalent cause of cancer-related death worldwide in 2018, and its incidence is increasing. While therapeutic agents for hepatic cancer have improved, these agents can cause serious side effects, including damage to healthy tissues. To overcome this limitation, more than 3,000 plants have been used globally as common alternatives for cancer treatment. The anti-cancer activity of Alpinia japonica, one of the traditional herbal medicines (Korean name: Kkot-yang-ha), was investigated. Water extract of A. japonica (AJ) decreased the cell viability of hepatic cancer cells. AJ extract showed greater than 70% loss of mitochondrial potential in HepG2 cells as demonstrated by JC-1 staining. Apoptosis was induced by treatment with AJ extract as shown through FACS analysis, and G0/G1 phase arrest of 76.66% HepG2 cells was confirmed through cell cycle analysis and quantitative RT-PCR. Improper regulation of ERK1/2 might contribute to cell death, and JNK activation is necessary for apoptosis induced by stress stimuli. AJ extract stimulated the phosphorylation of JNK and ERK1/2, mitogen-activated protein kinases (MAPKs), in HepG2 cells. AJ extract has anticancer activity by inhibiting cell cycle progression, leading to apoptosis of hepatic cancer cells. This extract could potentially be used as a therapeutic agent for hepatic cancer.


Assuntos
Alpinia , Carcinoma Hepatocelular , Neoplasias Hepáticas , Extratos Vegetais , Alpinia/química , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular , Neoplasias Hepáticas/tratamento farmacológico , Humanos , Células Hep G2 , Extratos Vegetais/farmacologia
16.
Life Sci Alliance ; 6(8)2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37197981

RESUMO

Connexin37-mediated regulation of cell cycle modulators and, consequently, growth arrest lack mechanistic understanding. We previously showed that arterial shear stress up-regulates Cx37 in endothelial cells and activates a Notch/Cx37/p27 signaling axis to promote G1 cell cycle arrest, and this is required to enable arterial gene expression. However, how induced expression of a gap junction protein, Cx37, up-regulates cyclin-dependent kinase inhibitor p27 to enable endothelial growth suppression and arterial specification is unclear. Herein, we fill this knowledge gap by expressing wild-type and regulatory domain mutants of Cx37 in cultured endothelial cells expressing the Fucci cell cycle reporter. We determined that both the channel-forming and cytoplasmic tail domains of Cx37 are required for p27 up-regulation and late G1 arrest. Mechanistically, the cytoplasmic tail domain of Cx37 interacts with, and sequesters, activated ERK in the cytoplasm. This then stabilizes pERK nuclear target Foxo3a, which up-regulates p27 transcription. Consistent with previous studies, we found this Cx37/pERK/Foxo3a/p27 signaling axis functions downstream of arterial shear stress to promote endothelial late G1 state and enable up-regulation of arterial genes.


Assuntos
Conexinas , Células Endoteliais , Células Endoteliais/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Conexinas/genética , Conexinas/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Núcleo Celular/metabolismo , Proteína alfa-4 de Junções Comunicantes
17.
Biosci Biotechnol Biochem ; 87(8): 825-832, 2023 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-37245061

RESUMO

The phytochemical investigation of Dialium corbisieri seeds led to the isolation of five monoterpenoid indole alkaloids along with a phytoserotonin, 1-6 and among the known compounds, the spectroscopic data of (5S)-methoxy-akuammiline (1) was reported for the first time. The structures were elucidated based on nuclear magnetic resonance spectroscopic techniques such as ultraviolet, infrared, high-resolution electrospray ionization time-of-flight mass spectrometry, and electron-capture dissociation spectrum calculations. The isolated compounds were evaluated for their cytotoxicity and cell progression in the human acute promyelocytic leukemia HL60 cell line.


Assuntos
Leucemia Promielocítica Aguda , Humanos , Células HL-60 , Leucemia Promielocítica Aguda/tratamento farmacológico , Estrutura Molecular , Alcaloides Indólicos/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular
18.
Front Immunol ; 14: 1127552, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37006313

RESUMO

Giardia duodenalis is a zoonotic intestinal protozoan parasite that may cause host diarrhea and chronic gastroenteritis, resulting in great economic losses annually and representing a significant public health burden across the world. However, thus far, our knowledge on the pathogenesis of Giardia and the related host cell responses is still extensively limited. The aim of this study is to assess the role of endoplasmic reticulum (ER) stress in regulating G0/G1 cell cycle arrest and apoptosis during in vitro infection of intestinal epithelial cells (IECs) with Giardia. The results showed that the mRNA levels of ER chaperone proteins and ER-associated degradation genes were increased and the expression levels of the main unfolded protein response (UPR)-related proteins (GRP78, p-PERK, ATF4, CHOP, p-IRE1, XBP1s and ATF6) were increased upon Giardia exposure. In addition, cell cycle arrest was determined to be induced by UPR signaling pathways (IRE1, PERK and ATF6) through upregulation of p21 and p27 levels and promotion of E2F1-RB complex formation. Upregulation of p21 and p27 expression was shown to be related to Ufd1-Skp2 signaling. Therefore, the cell cycle arrest was induced by ER stress when infected with Giardia. Furthermore, the apoptosis of the host cell was also assessed after exposure to Giardia. The results indicated that apoptosis would be promoted by UPR signaling (PERK and ATF6), but would be suppressed by the hyperphosphorylation of AKT and hypophosphorylation of JNK that were modulated by IRE1 pathway. Taken together, both of the cell cycle arrest and apoptosis of IECs induced by Giardia exposure involved the activation of the UPR signaling. The findings of this study will deepen our understanding of the pathogenesis of Giardia and the associated regulatory network.


Assuntos
Giardia lamblia , Giardia lamblia/genética , Pontos de Checagem da Fase G1 do Ciclo Celular , Estresse do Retículo Endoplasmático/fisiologia , Apoptose , Proteínas Serina-Treonina Quinases/metabolismo
19.
Naunyn Schmiedebergs Arch Pharmacol ; 396(10): 2481-2500, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37083712

RESUMO

Neuroblastoma is one of the most common solid tumors in children younger than 1 year of age, with poor prognosis and survival rates. Therefore, novel molecular targets and therapeutic strategies are needed to prolong patient survival. For this purpose, we investigated the effects of rottlerin and genistein separately and in combination on neuroblastoma cells (SH-SY5Y, Kelly). First, the effects of rottlerin and genistein were investigated on cell proliferation. Different rottlerin (1-50 µM) and genistein (5-150 µM) doses were used as experimental groups compared to the control (DMSO/vehicle). The IC50 dose was found to be 5 µM for rottlerin and 30 µM for genistein (P < 0.0001). Other analyses, such as colony formation assays, annexin V/propidium iodide staining, matrigel invasion assays, and Western blot analysis, were performed with these doses and their combinations. To assess statistical significance, statistical analysis was conducted using the one-way ANOVA with the post hoc Tukey test. Our results showed that IC50 doses of rottlerin and genistein induced a significant reduction in cell proliferation, colony formation, and invasion in neuroblastoma cells (P < 0.0001). The combination of these doses increased the levels of inhibition of cell proliferation and invasion while decreasing the level of apoptosis (P 0.0001). Furthermore, these agents caused G1-cell cycle arrest in these cells. Our western blot data showed that rottlerin and genistein treatments markedly inhibit elongation factor 2 kinase (EF2K) and other pro-tumorigenic, metastatic proteins in neuroblastoma cells. These agents probably showed their anti-proliferative, anti-metastatic, and pro-apoptotic effects through EF2K downregulation. Our results suggested that rottlerin and genistein have inhibitory effects on cancer cell proliferation, invasion, and cell cycle and induce apoptosis in both cell lines. Combined treatment with rottlerin and genistein may be a viable approach and beneficial to neuroblastoma patients as the combined effect significantly suppresses the above-mentioned pathways.


Assuntos
Genisteína , Neuroblastoma , Criança , Humanos , Genisteína/farmacologia , Genisteína/uso terapêutico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Quinase do Fator 2 de Elongação , Proliferação de Células , Apoptose , Pontos de Checagem da Fase G1 do Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular
20.
Clin Exp Metastasis ; 40(2): 161-175, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36952079

RESUMO

Brain metastasis is the main cause of treatment failure and melanoma-related death. Inadequate concentrations of therapeutic drugs in the brain due to the blood-brain barrier (BBB) pose a major challenge in the treatment of brain metastasis. Antipsychotics can cross the BBB to reach the brain. Fluphenazine (FPZ) inhibits the survival of melanoma cells in vitro. However, its efficacy in suppressing the metastasis of melanoma, especially brain metastasis, remains unknown. Therefore, we explored whether fluphenazine (FPZ) can be repurposed for treating melanoma metastasis. A subcutaneous tumor model, and experimental metastasis models that simulate the outgrowth of melanoma cells in the brain, lung, and bone were established to verify the inhibitory effect of FPZ on melanoma cells. FPZ showed potential inhibitory effects against melanoma both in vivo and in vitro. It induced G0/G1 phase arrest and-mitochondrion-mediated intrinsic apoptosis, and inhibited autophagic flux in melanoma cells in vitro. In vivo, subcutaneous tumor, brain, lung, and bone models of metastatic melanoma were established. Intraperitoneal injection of FPZ (8 mg/kg) significantly inhibited melanoma growth in the subcutaneous and experimental metastasis models. In a lung metastasis model, FPZ reduced the proportion of M2 macrophages and increased the proportion of CD8+ T cells and NK cells in vivo, thereby promoting an anticancer immune response. The findings of this study indicate that FPZ is a potential drug candidate for treating metastatic melanoma.


Assuntos
Neoplasias Encefálicas , Melanoma , Humanos , Flufenazina/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular , Linfócitos T CD8-Positivos/patologia , Reposicionamento de Medicamentos , Melanoma/tratamento farmacológico , Melanoma/patologia , Encéfalo/patologia , Neoplasias Encefálicas/tratamento farmacológico , Pulmão/patologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células
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