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1.
J Med Virol ; 96(7): e29752, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38949191

RESUMO

Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.


Assuntos
COVID-19 , Mitocôndrias , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Mitocôndrias/metabolismo , COVID-19/metabolismo , COVID-19/virologia , COVID-19/patologia , Células A549 , Proteínas Virais Reguladoras e Acessórias/metabolismo , Proteínas Virais Reguladoras e Acessórias/genética , Transcriptoma , Fases de Leitura Aberta , Proteínas Virais/genética , Proteínas Virais/metabolismo , Proteínas Viroporinas
2.
Front Immunol ; 14: 1220306, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37545510

RESUMO

SARS-CoV-2, the cause of the COVID-19 pandemic, possesses eleven accessory proteins encoded in its genome. Their roles during infection are still not completely understood. In this study, transcriptomics analysis revealed that both WNT5A and IL11 were significantly up-regulated in A549 cells expressing individual accessory proteins ORF6, ORF8, ORF9b or ORF9c from SARS-CoV-2 (Wuhan-Hu-1 isolate). IL11 is a member of the IL6 family of cytokines. IL11 signaling-related genes were also differentially expressed. Bioinformatics analysis disclosed that both WNT5A and IL11 were involved in pulmonary fibrosis idiopathic disease and functional assays confirmed their association with profibrotic cell responses. Subsequently, data comparison with lung cell lines infected with SARS-CoV-2 or lung biopsies from patients with COVID-19, evidenced altered profibrotic gene expression that matched those obtained in this study. Our results show ORF6, ORF8, ORF9b and ORF9c involvement in inflammatory and profibrotic responses. Thus, these accessory proteins could be targeted by new therapies against COVID-19 disease.


Assuntos
COVID-19 , Interleucina-11 , SARS-CoV-2 , Proteínas Virais , Humanos , SARS-CoV-2/genética , Proteínas Virais/genética , Fibrose Pulmonar Idiopática
3.
Int J Clin Exp Pathol ; 8(3): 2888-98, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26045797

RESUMO

Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancers, which are the leading cause of cancer-related deaths in the world. Tyrosine kinase inhibitors such as erlotinib represent one therapeutic options presently recommended for tumors produced by activating mutations in the gene coding of epidermal growth factor receptor (EGFR). The aim of this study is the identification of possible biomarkers for tumor sensitivity to erlotinib in the absence of the main EGFR mutations. The erlotinib sensitivity of cells isolated from 41 untreated NSCLC patients was determined and compared with the presence of the more frequent EGFR mutations. Several patients had tumor cells highly sensitive to erlitinib in the absence of the EGFR mutations analyzed. The gene expression profile of 3 erlotinib-sensitive tumors was compared with that of 4 resistant tumors by DNA microarray hybridization. Sixteen genes were expressed at significantly higher levels in the resistant tumors than in the sensitive tumors. The possible correlation between erlotinib sensitivity and the expression of these genes was further analyzed using the data for the NSCLC, breast cancer and colon cancer cell lines of the NCI60 collection. The expression of these genes was correlated with the overall survival of 5 patients treated with erlotinib, according to The Cancer Genome Atlas (TCGA) database. Overlapping groups of 7, 5 and 3 genes, including UGT1A6, TRIB3, MET, MMP7, COL17A1, LCN2 and PTPRZ1, whose expression correlated with erlotinib activity was identified. In particular, low MET expression levels showed the strongest correlation.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma
4.
Cancer Med ; 3(5): 1099-111, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24961511

RESUMO

Lung cancer is the top cause of cancer-related deceases. One of the reasons is the development of resistance to the chemotherapy treatment. In particular, cancer stem cells (CSCs), can escape treatment and regenerate the bulk of the tumor. In this article, we describe a comparison between cancer cells resistant to cisplatin and CSCs, both derived from the non-small-cell lung cancer cell lines H460 and A549. Cisplatin-resistant cells were obtained after a single treatment with the drug. CSCs were isolated by culture in defined media, under nonadherent conditions. The isolated CSCs were clonogenic, could be differentiated into adherent cells and were less sensitive to cisplatin than the original cells. Cisplatin resistant and CSCs were able to generate primary tumors and to metastasize when injected into immunodeficient Nu/Nu mice, although they formed smaller tumors with a larger latency than untreated cells. Notably, under appropriated proportions, CSCs synergized with differentiated cells to form larger tumors. CSCs also showed increased capacity to induce angiogenesis in Nu/Nu mice. Conversely, H460 cisplatin-resistant cells showed increased tendency to develop bone metastasis. Gene expression analysis showed that several genes involved in tumor development and metastasis (EGR1, COX2, MALAT1, AKAP12, ADM) were similarly induced in CSC and cisplatin-resistant H460 cells, in agreement with a close similarity between these two cell populations. Cells with the characteristic growth properties of CSCs were also isolated from surgical samples of 18 out of 44 lung cancer patients. A significant correlation (P = 0.028) was found between the absence of CSCs and cisplatin sensitivity.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Camundongos , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Neovascularização Patológica , Ensaio Tumoral de Célula-Tronco
5.
Clin Transl Oncol ; 13(5): 289-93, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21596655

RESUMO

The cancer stem cell (CSC) theory is currently a very important field in cancer research. This theory states that tumours are organised in a hierarchical manner with a subpopulation of limited number called CSCs with the ability to self-renew and undergo asymmetrical divisions, giving rise to a differentiated progeny that represents most of the tumour populations. CSCs are metastatic and chemoresistant, two features that very likely contribute to the poor response of locally advanced lung cancer. CSCs have been identified in non-small-cell lung cancer cell lines as well as those from patient primary samples. A correlation has been found in terms of chemoresistance and bad prognosis in patient-derived samples enriched with CSCs, indicating that these cells are an important target for future therapy combinations. Therefore, understanding the biology and exploring cell markers and signalling pathways specific for CSCs of lung cancer may help in achieving progress in the treatment of the disease.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/citologia , Antígeno AC133 , Aldeído Desidrogenase/metabolismo , Antígenos CD/biossíntese , Antígenos CD34/biossíntese , Diferenciação Celular , Glicoproteínas/biossíntese , Humanos , Receptores de Hialuronatos/biossíntese , Oncologia/métodos , Metástase Neoplásica , Peptídeos , Transdução de Sinais , Fatores de Transcrição/metabolismo , Resultado do Tratamento
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