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1.
Methods Mol Biol ; 2571: 45-55, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36152149

RESUMO

This methodological work demonstrates the potential of metabolomic approaches based on liquid chromatography coupled to high-resolution mass spectrometry (LC-ESI(+/-)-HRMS) to investigate the antiproliferative capacity of underexplored biomasses (e.g., Passiflora mollissima seeds and Physalys peruviana calyx), by evaluating the molecular changes induced at the metabolite expression levels on HT-29 human colon cancer cells. This protocol describes in detail the optimal conditions to obtain bioactive extracts by pressurized liquid extraction (PLE), the experimental procedure to grow and treat HT-29 human colon cancer cells and CCD-18Co normal human colon fibroblasts with the target extracts, the metabolites extraction from the cytosolic fraction, and subsequent metabolomic fingerprinting. After treatment for 48 and 72 h, the viability of HT-29 colon cancer cells is markedly affected, and metabolites can be extracted for investigation. Following the proposed metabolomic data analysis and interpretation workflow, altered cellular redox homeostasis, as well as inactivation or dysfunction on other metabolic pathways, constitutes valuable biological information to understand the mechanisms underlying the antiproliferative effect.


Assuntos
Neoplasias do Colo , Frutas , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Frutas/metabolismo , Humanos , Metabolômica/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia
2.
Med Sci (Basel) ; 10(4)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36412903

RESUMO

BACKGROUND: 5-Fluorouracil (5-FU) represents one of the major constituents of chemotherapy combination regimens in colon cancer (CRC) treatments; however, this regimen is linked with severe adverse effects and chemoresistance. Thus, developing more efficient approaches for CRC is urgently needed to overcome these problems and improve the patient survival rate. Currently, 17ß-estradiol (E2) has gained greater attention in colon carcinogenesis, significantly lowering the incidence of CRC in females at reproductive age compared with age-matched males. AIMS: This study measured the effects of E2 and/or 5-FU single/dual therapies on cell cycle progression and apoptosis against human HT-29 female and SW480 male primary CRC cells versus their impact on SW620 male metastatic CRC cells. METHODS: The HT-29, SW480, and SW620 cells were treated with IC50 of E2 (10 nM) and 5-FU (50 µM), alone or combined (E+F), for 48 h before cell cycle and apoptosis analyses using flow cytometry. RESULTS: The data here showed that E2 monotherapy has great potential to arrest the cell cycle and induce apoptosis in all the investigated colon cancer cells, with the most remarkable effects on metastatic cells (SW620). Most importantly, the dual therapy (E+F) has exerted anti-cancer activities in female (HT-29) and male (SW480) primary CRC cells by inducing apoptosis, which was preferentially provoked in the sub-G1 phase. However, the dual treatment showed the smallest effect in SW620 metastatic cells. CONCLUSION: this is the first study that demonstrated that the anti-cancer actions of 17ß-estradiol and 5-Fluorouracil dual therapy were superior to the monotherapies in female and male primary CRC cells; it is proposed that this treatment strategy could be promising for the early stages of CRC. At the same time, 17ß-estradiol monotherapy could be a better approach for treating the metastatic forms of the disease. Nevertheless, additional investigations are still required to determine their precise therapeutic values in CRC.


Assuntos
Neoplasias do Colo , Fluoruracila , Masculino , Feminino , Humanos , Fluoruracila/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HT29 , Apoptose , Estradiol/farmacologia , Estradiol/uso terapêutico
3.
Front Immunol ; 13: 1018334, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341436

RESUMO

Amino acid metabolism is closely related to the occurrence and development of colon adenocarcinoma (COAD). Studies on the relationship between COAD and the expression of amino acid metabolism are still rare. Based on in silico analysis, we used 358 amino acid metabolism-related genes (AAMRGs) to determine the amino acid metabolism characteristics and then classified COAD into two distinct subtypes, namely AA1 and AA2. Then we analyzed the clinical characteristics, somatic mutation landscape, transcriptome profile, metabolism signatures, immune infiltration, and therapy sensitivity of these two subtypes. The AA1 subtype had inferior overall survival and was characterized by lower amino acid metabolic activity, higher tumor mutation burden, and higher immune cell infiltration, while AA2 displayed higher metabolic activity and relatively better survival. Furthermore, the AA1 subtype was likely to benefit from irinotecan in chemotherapy and immune checkpoint blockade therapy including programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) immune checkpoint inhibitor but was resistant to targeted therapy cetuximab. The AA2 subtype showed higher sensitivity to 5-fluorouracil and oxaliplatin. To provide perspectives on cell-specific metabolism for further investigation, we explored metabolic activity in different cell types including lymphocytes, mast cells, myeloid cells stromal cells, and epithelial cells via colorectal cancer single-cell data. Additionally, to assist in clinical decision-making and prognosis prediction, a 60-AAMRG-based classifier was generated and validated in an independent cohort.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Humanos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Prognóstico , Aminoácidos
4.
Cell Death Dis ; 13(10): 888, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36270986

RESUMO

Histone deacetylase 6 (HDAC6), a member of the HDAC family, has been identified as a potential therapeutic target for tumor therapy, but the function and underlying mechanisms of HDAC6 in colon cancer are incompletely characterized. Our study showed that the infiltration ratio of M2 macrophages was increased in colon cancer tissues with high HDAC6 expression. Similarly, the knockdown of HDAC6 in colon cancer cells inhibited cocultured macrophage M2 polarization in vitro. Analysis of the antibody chip revealed that HDAC6 promoted sIL-6R release to enhance macrophage M2 polarization. Mass spectrometry and immunoprecipitation demonstrated that, mechanistically, HDAC6 interacted with transforming growth factor ß-activated kinase 1 (TAK1), deacetylated TAK1 at T178 and promoted TAK1 phosphorylation. TAK1-p38 MAPK signaling could further increase the phosphorylation and activity of ADAM17, which is responsible for shedding of IL-6R. Notably, the expression of phosphorylated TAK1 was positively correlated with HDAC6 expression and macrophage M2 polarization in human colon cancer tissues. Our study revealed a new HDAC6-TAK1-ADAM17 regulatory axis that mediates sIL-6R release and macrophage polarization in colon cancer.


Assuntos
Neoplasias do Colo , Humanos , Neoplasias do Colo/metabolismo , Desacetilase 6 de Histona/metabolismo , Macrófagos/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fator de Crescimento Transformador beta/metabolismo
5.
Anticancer Res ; 42(11): 5385-5396, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36288851

RESUMO

BACKGROUND/AIM: Most deaths from colon cancer are due to metastasis. Recently, PGE2 was found to influence colon cancer invasion and metastasis. 15-PGDH, an enzyme that metabolizes PGE2, is known as a tumor suppressor in colonic carcinogenesis. This study investigated the effect of 15-PGDH on colon cancer metastasis. MATERIALS AND METHODS: 15-PGDH expression by immunohistochemical staining, clinicopathologic features, and 5-year cancer-specific survival were investigated in colon cancer patients. Liver metastasis was examined by assaying 15-PGDH activity in an animal model. Changes in PGE2, proliferation, migration, and invasion of the colorectal cancer cell line HCT116, were examined using a 15-PGDH inhibitor (SW033291) or enhancer (CDDO-ME). The expression of genes involved in the epithelial-to-mesenchymal transition (EMT) was also studied. RESULTS: The absence of 15-PGDH expression significantly correlated with advanced-stage, lymph node metastasis, and decreased cancer-specific survival in colon cancer patients. Inhibition of 15-PGDH increased colon cancer liver metastasis in the animal model. The 15-PGDH inhibitor, SW033291, increased PGE2 and decreased 15-PGDH expression on HCT116. However, treatment with CDDO-ME, a substance that enhances 15-PGDH, showed the opposite results. Inhibition of 15-PGDH increased cell proliferation, migration, and invasion, but activation of 15-PGDH showed the opposite effect. Inhibition of 15-PGDH also affected the EMT markers, N-cadherin, Snail, and Twist2. CONCLUSION: 15-PGDH inhibition increased colon cancer metastasis by inducing changes in EMT-related genes via an increase in PGE2 expression and could be a promising biomarker for anticancer treatment.


Assuntos
Neoplasias do Colo , Neoplasias Hepáticas , Animais , Regulação para Cima , Dinoprostona/metabolismo , Hidroxiprostaglandina Desidrogenases/genética , Hidroxiprostaglandina Desidrogenases/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Transição Epitelial-Mesenquimal/genética , Caderinas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica
6.
Biomed Res Int ; 2022: 4009354, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36254139

RESUMO

As the largest gene family functioning in protein transport among human solute carriers, the SLC25 family (mitochondrial carrier family) can participate in development of cancer. However, a comprehensive exploration for the exactly roles of SLC family remains lacking. In the present study, a total of 15 functional SLC25 family genes were retrieved from all current publications. And multidimensional analyses were systematically performed based on the transcriptome and genome data of SLC25 family from a variety of online databases for their expression, immune cell infiltration, and cancer prognosis. Validation by qPCR and immunohistochemistry were further conducted for the expression of partial SLC25 family members in some tumor tissue. We found that the SLC25 family had strong correlation with immune cells, such as macrophages M2, CD8+ T cell, CD4+ T cell memory activated, and memory resting. Among them, SLC25A6 was most correlated with Macrophage M1 in uveal melanoma (r = -0.68, P = 1.9e - 0.5). Expression of mRNA level showed that SLC25A4 was downregulated in stomach adenocarcinoma and colon adenocarcinoma. SLC25A7 was highly expressed in stomach adenocarcinoma and colon adenocarcinoma. SLC25A23 was decreased in colon adenocarcinoma. qPCR and immunohistochemistry validation results were consistent with our bioinformatics prediction. SLC25A8 was associated with the prognosis of cancer. All these findings suggested that the SLC25 family might affects the immune microenvironment of the cancer and then had the potential to be predictive biomarkers for early diagnosis and prognosis as well as novel targets for individualized treatment of cancer.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Adenocarcinoma/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Humanos , Mitocôndrias/metabolismo , Prognóstico , RNA Mensageiro/metabolismo , Microambiente Tumoral/genética
7.
Lancet Digit Health ; 4(11): e787-e795, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36307192

RESUMO

BACKGROUND: Digital whole-slide images are a unique way to assess the spatial context of the cancer microenvironment. Exploring these spatial characteristics will enable us to better identify cross-level molecular markers that could deepen our understanding of cancer biology and related patient outcomes. METHODS: We proposed a graph neural network approach that emphasises spatialisation of tumour tiles towards a comprehensive evaluation of predicting cross-level molecular profiles of genetic mutations, copy number alterations, and functional protein expressions from whole-slide images. We introduced a transformation strategy that converts whole-slide image scans into graph-structured data to address the spatial heterogeneity of colon cancer. We developed and assessed the performance of the model on The Cancer Genome Atlas colon adenocarcinoma (TCGA-COAD) and validated it on two external datasets (ie, The Cancer Genome Atlas rectum adenocarcinoma [TCGA-READ] and Clinical Proteomic Tumor Analysis Consortium colon adenocarcinoma [CPTAC-COAD]). We also predicted microsatellite instability and result interpretability. FINDINGS: The model was developed on 459 colon tumour whole-slide images from TCGA-COAD, and externally validated on 165 rectum tumour whole-slide images from TCGA-READ and 161 colon tumour whole-slide images from CPTAC-COAD. For TCGA cohorts, our method accurately predicted the molecular classes of the gene mutations (area under the curve [AUCs] from 82·54 [95% CI 77·41-87·14] to 87·08 [83·28-90·82] on TCGA-COAD, and AUCs from 70·46 [61·37-79·61] to 81·80 [72·20-89·70] on TCGA-READ), along with genes with copy number alterations (AUCs from 81·98 [73·34-89·68] to 90·55 [86·02-94·89] on TCGA-COAD, and AUCs from 62·05 [48·94-73·46] to 76·48 [64·78-86·71] on TCGA-READ), microsatellite instability (MSI) status classification (AUC 83·92 [77·41-87·59] on TCGA-COAD, and AUC 61·28 [53·28-67·93] on TCGA-READ), and protein expressions (AUCs from 85·57 [81·16-89·44] to 89·64 [86·29-93·19] on TCGA-COAD, and AUCs from 51·77 [42·53-61·83] to 59·79 [50·79-68·57] on TCGA-READ). For the CPTAC-COAD cohort, our model predicted a panel of gene mutations with AUC values from 63·74 (95% CI 52·92-75·37) to 82·90 (73·69-90·71), genes with copy number alterations with AUC values from 62·39 (51·37-73·76) to 86·08 (79·67-91·74), and MSI status prediction with AUC value of 73·15 (63·21-83·13). INTERPRETATION: We showed that spatially connected graph models enable molecular profile predictions in colon cancer and are generalised to rectum cancer. After further validation, our method could be used to infer the prognostic value of multiscale molecular biomarkers and identify targeted therapies for patients with colon cancer. FUNDING: This research has been partially funded by ARO MURI 805491, NSF IIS-1793883, NSF CNS-1747778, NSF IIS 1763523, DOD-ARO ACC-W911NF, and NSF OIA-2040638 to Dimitri N Metaxas.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Humanos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Regulação Neoplásica da Expressão Gênica , Instabilidade de Microssatélites , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteômica , Estudos de Coortes , Estudos Retrospectivos , Redes Neurais de Computação , Microambiente Tumoral
8.
Front Biosci (Landmark Ed) ; 27(9): 263, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36224007

RESUMO

Cancer progression and metastases are the leading causes of poor outcomes in patients with colon cancer. Colon cancer metastasis is a multigene, multistep, multistage complex process in which target genes, microRNAs, epithelial-stromal transformation, tumour stem cells, the tumour microenvironment, and various cell signalling pathways are implicated in the progression and metastasis of colon cancer. Although conventional therapies have made significant advances in treating the progression and metastasis of colorectal cancer, they have failed to improve survival outcomes. Natural compounds may have more significant potential in preventing and treating colon cancer. Active natural compounds exert their antitumor effects by inducing tumour cell differentiation, promoting tumour cell apoptosis, inhibiting tumour vascular growth, and regulating immunity. Natural compounds, combined with conventional therapies, can target mutant genes and various cellular signalling pathways, inhibit epithelial-stromal transformation, and improve the tumour microenvironment to inhibit tumour progression and metastasis. The synergism of natural compounds and conventional therapeutics has the potential to become a promising therapy for treating colorectal cancer progression and metastases.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , MicroRNAs , Apoptose , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Metástase Neoplásica , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral
9.
Sci Rep ; 12(1): 17571, 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36266428

RESUMO

The E3 ubiquitin-ligases are important for cellular protein homeostasis and their deregulation is implicated in cancer. The E3 ubiquitin-ligase Hakai is involved in tumour progression and metastasis, through the regulation of the tumour suppressor E-cadherin. Hakai is overexpressed in colon cancer, however, the implication in colitis-associated cancer is unknown. Here, we investigated the potential role of Hakai in intestinal inflammation and cancer bowel disease. Several mouse models of colitis and associated cancer were used to analyse Hakai expression by immunohistochemistry. We also analysed Hakai expression in patients with inflamed colon biopsies from ulcerative colitis and Crohn's disease. By Hakai interactome analysis, it was identified Fatty Acid Synthase (FASN) as a novel Hakai-interacting protein. Moreover, we show that Hakai induces FASN ubiquitination and degradation via lysosome, thus regulating FASN-mediated lipid accumulation. An inverse expression of FASN and Hakai was detected in inflammatory AOM/DSS mouse model. In conclusion, Hakai regulates FASN ubiquitination and degradation, resulting in the regulation of FASN-mediated lipid accumulation, which is associated to the development of inflammatory bowel disease. The interaction between Hakai and FASN may be an important mechanism for the homeostasis of intestinal barrier function and in the pathogenesis of this disease.


Assuntos
Colite , Neoplasias do Colo , Ubiquitina-Proteína Ligases , Animais , Camundongos , Caderinas/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ácido Graxo Sintases , Inflamação , Lipídeos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinas , Colite/complicações , Colite/metabolismo
10.
Med Oncol ; 39(12): 251, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224472

RESUMO

Over the last few decades, the number of people diagnosed with cancer has increased dramatically every year, making it a major cause of mortality today. Colon cancer is the third most common cancer worldwide, and the second in mortality rate. Current cancer treatment fails to treat colon cancer completely due to the remains of Cancer Stem Cells (CSCs). Morin flavonoid present in figs (Ficus carica) and other plant sources, was found to have an anti-proliferative effect on the colon cancer model and cell line, but it is not studied for its effect on the colon CSCs. In this study, we have tested the potency of morin to inhibit CSCs. We found that morin has significantly reduced colon cancer cell proliferation, colony formation, migration, and colonospheroid formation in a dose-dependent manner. Pumilio-1 (PUM1) has been shown to play an important role in colon CSCs maintenance. We found that morin has a good binding affinity with PUM1 protein with one hydrophobic and two hydrogen bond interactions. Further, the immunofluorescence results have also shown a reduction in PUM1 expression in colon cancer cell lines after morin treatment. CD133 is overexpressed in colon CSCs and morin treatment has reduced the CD133 expression in HCT116 and CT26 colon cancer cell lines. Our research outcome has explored the anti-cancer stem cell potency of morin via targeting the PUM1 protein and further reducing the colon spheroids formation and reducing the CD133 expression in colon cancer cells.


Assuntos
Neoplasias do Colo , Células-Tronco Neoplásicas , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Flavonas , Flavonoides/farmacologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Proteínas de Ligação a RNA/metabolismo
11.
Toxicol Appl Pharmacol ; 456: 116256, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36208702

RESUMO

Colorectal cancer (CRC) is estimated as the third most incident cancer and second in mortality worldwide. Moreover, CRC metastasis reduces patients' survival rates. Thus, the study and identification of new compounds with anticancer activity selectively to tumor cells are encouraged in the CRC treatment. Naphtoquinones are compounds with several pharmacologic activities, including antitumoral properties. Therefore, this study aimed to investigate the anticancer mechanism of synthetic 8-Hydroxy-2-(P-Nitrothiophenol)-1,4-Naphthoquinone (CNN16) in colon cancer cell line HCT-116. CNN16 showed an IC50 of 5.32 µM in HCT-116, and 9.36, 10.77, and 24.57 µM in the non-cancerous cells MRC-5, MNP-01, and PMBC, respectively, evaluated by the MTT assay. CNN16 showed an anticlonogenic effect in HCT-116 and induced cell fragmentation identified by flow cytometry analysis. Furthermore, we observed that CNN16 presented genotoxicity and induces reactive oxygen species (ROS) after 3 h of treatment visualized by alkaline comet assay and DCFH-DA dye fluorescence, respectively. Furthermore, CNN16 caused cellular membrane disruption, reduction in the mitochondrial membrane polarization, and the presence of apoptotic bodies and chromatin condensation was visualized by differential stained (HO/FD/PI) in fluorescent microscopy along with PARP1, TP53, BCL-2, and BAX analyzed by RT-qPCR. Results also evidenced inhibition in the migratory process analyzed by wound healing assay. Therefore, CNN16 can be considered as a potential new leader molecule for CRC treatment, although further studies are still necessary to comprehend the effects of CNN16 in in vivo models to evaluate the anti-migratory effect, and toxicology and assure compound safety and selectively.


Assuntos
Antineoplásicos , Neoplasias do Colo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular , Antineoplásicos/farmacologia , Apoptose , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Linhagem Celular , Dano ao DNA , Naftalenos/farmacologia , Linhagem Celular Tumoral , Potencial da Membrana Mitocondrial
12.
Artigo em Inglês | MEDLINE | ID: mdl-36244213

RESUMO

INTRODUCTION: Several studies have shown the antiproliferative effect of iodine and 5­hydroxy-6 iodo-eicosatrienoic delta lactone (IL-δ) on diverse tissues. It was demonstrated that molecular iodine (I2) and IL-δ, but not iodide (I-), exerts anti-neoplastic actions in different cancers. The underlying mechanism through which IL-δ inhibits tumor growth remains unclear. The aim of this study was to analyze the effect of IL-δ on tumor growth and angiogenesis in human HT29 colorectal cancer xenografts. METHODOLOGY AND RESULTS: HT29 cells were injected subcutaneously into the flanks of nude mice and IL-δ was i.p. injected at a dose of 15 µg three days a week. IL-δ treatment in HT29 xenografts showed time-dependent inhibition of tumor growth, decrease of mitosis and PCNA expression (p < 0.05), increase of P27 expression and Caspase 3 activity after 18 days of treatment (p < 0.05). To assess tumor Microvessel Densities (MVD), CD31 staining by immunohistochemistry was analyzed. IL-δ treatment decreased MVD by 17% and 30% after 18 and 30 days respectively (p < 0.05), as well as it decreased VEGF and VEGF-R2 expression (p < 0.05). Additionally, our findings demonstrated that IL-δ increased VEGF-R1 and Ang-1 mRNA levels (p < 0.01). CONCLUSION: The antitumor efficacy of IL-δ in vivo involves inhibition of cell proliferation as well as induction of apoptosis. IL-δ has also anti-angiogenic effect associated with VEGF and VEGF-R2 downregulation followed by Ang-1 and VEGF-R1 increased expression. High levels of Ang-1 would contribute to mature vessel stabilization and maintenance while VEGF-R1 increase would produce anti-proliferative effect on endothelial cells.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Iodo , Camundongos , Animais , Humanos , Células HT29 , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Camundongos Nus , Xenoenxertos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Células Endoteliais/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Neovascularização Patológica/tratamento farmacológico , Lactonas/uso terapêutico , Iodo/uso terapêutico , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C
13.
Ann Clin Lab Sci ; 52(4): 571-579, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36197770

RESUMO

OBJECTIVE: The NLRP3 inflammasome plays a key role in the progression and metastasis of colorectal cancer (CRC). METHODS: Macrophages (MΦs), as an important cellular component of the tumor microenvironment (TME), highly express the NLRP3 inflammasome. Rigorous investigation of the interaction and network between macrophages and colorectal cancer may help in understanding the role of the NLRP3 inflammasome in metastatic colorectal cancer. RESULTS: Herein, we demonstrated that NLRP3 inflammasome activation in MΦs-CRC crosstalk markedly promotes the invasion, migration, and epithelial-mesenchymal transition (EMT) of colorectal cancer cells in vitro. MΦs-CRC crosstalk activated the NLRP3 inflammasome to secrete the proinflammatory cytokine IL-1ß. Notably, IL-1ß neutralizing antibody (NA) weakened the invasion and migration promotion effects of MΦs-CRC crosstalk in vitro. Based on Spearman's rank correlation analysis, we found that the expression of NLRP3 was positively associated with the expression of the macrophage surface marker CD68 and the proinflammatory cytokine IL-1ß. Clinical investigations suggested that the expression of NLRP3 in patients with colorectal cancer was positively associated with advanced AJCC stage and poor prognosis. CONCLUSION: This study found that the activation of the NLRP3 inflammasome in macrophages can secrete the proinflammatory cytokine IL-1ß to promote the invasion and migration of colorectal cancer cells by regulating epithelial-mesenchymal transition (EMT). This research provides a new strategy for developing the NLRP3 inflammasome as a potential therapeutic target to prevent metastatic colorectal cancer.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Inflamassomos , Anticorpos Neutralizantes , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/metabolismo , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Microambiente Tumoral
14.
Int J Mol Sci ; 23(20)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36293209

RESUMO

Human mitochondrial transcription termination factor 1 (MTERF1) has been demonstrated to play an important role in mitochondrial gene expression regulation. However, the molecular mechanism of MTERF1 in colorectal cancer (CRC) remains largely unknown. Here, we found that MTERF1 expression was significantly increased in colon cancer tissues compared with normal colorectal tissue by Western blotting, immunohistochemistry, and tissue microarrays (TMA). Overexpression of MTERF1 in the HT29 cell promoted cell proliferation, migration, invasion, and xenograft tumor formation, whereas knockdown of MTERF1 in HCT116 cells appeared to be the opposite phenotype to HT29 cells. Furthermore, MTERF1 can increase mitochondrial DNA (mtDNA) replication, transcription, and protein synthesis in colorectal cancer cells; increase ATP levels, the mitochondrial crista density, mitochondrial membrane potential, and oxygen consumption rate (OCR); and reduce the ROS production in colorectal cancer cells, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS) activity. Mechanistically, we revealed that MTERF1 regulates the AMPK/mTOR signaling pathway in cancerous cell lines, and we also confirmed the involvement of the AMPK/mTOR signaling pathway in both xenograft tumor tissues and colorectal cancer tissues. In summary, our data reveal an oncogenic role of MTERF1 in CRC progression, indicating that MTERF1 may represent a new therapeutic target in the future.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proliferação de Células/genética , DNA Mitocondrial/genética , Mitocôndrias/metabolismo , Células HCT116 , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Trifosfato de Adenosina/metabolismo , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica
15.
Int J Mol Sci ; 23(19)2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36232920

RESUMO

Colorectal cancer is a common cancer with a poor prognosis in both males and females. The influence of bisphenol A (BPA), a widely used environmental contaminant, in colon cancer development and progression is not well identified, in spite of the fact that the most common mode of exposure to BPA is ingestion. The aim of this work is to elucidate the carcinogenic effects of BPA in the colon in vitro. We analyzed BPA's effects on human colon epithelial (HCoEpiC) and colon cancer (HCT116) cells. BPA exerted cytotoxic effects and augmented the 5FU cytotoxicity on both cell lines at high doses, while it did not show this effect at low doses. Therefore, we focused on studying the effects of low-dose (0.0043 nM) exposure on normal colonic epithelial cells for a long period of time (two months), which is more consistent with environmental exposure levels and patterns. BPA increased cellular invasiveness through collagen and the ability to anchorage-independent cell growth, as measured by colony formation in soft agar, which could support oncogenicity. To gain insights into the mechanism of these actions, we performed transcriptomic analysis using next-generation sequencing, which revealed 340 differentially expressed transcripts by BPA in HCT116 and 75 in HCoEpiC. These transcripts belong in many cancer-related pathways such as apoptosis, cell proliferation, signal transduction, and angiogenesis. Some of the significant genes (FAM83H, CXCL12, PITPNA, HMOX1, DGKZ, NR5A2, VMP1, and ID1) were confirmed by quantitative RT-PCR. Furthermore, BPA induced the phosphorylation of protein kinases such as JNK1/2/3, GSK-3α/ß, AMPKα1, AKT1/2/3, AMPKα2, HSP27, ß-catenin, STAT2, Hck, Chk2, FAK, and PRAS40 in HCoEpiC, as well as GSK-3α/ß, p53, AKT1/2/3, p70 S6 kinase, and WNK1 in HCT116. The majority of these proteins are involved in potential carcinogenic pathways. Taken together, these data suggest that BPA plays a role in colon carcinogenesis, and they provide insights into the molecular mechanisms of colon epithelial cell transformation by BPA. Increasing exposure to environmental toxins such as BPA can explain the increasing incidence of colorectal cancer.


Assuntos
Neoplasias do Colo , beta Catenina , Ágar , Compostos Benzidrílicos/toxicidade , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Fluoruracila , Células HCT116 , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Membrana Mucosa/metabolismo , Fenóis , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/metabolismo
16.
Toxicol Appl Pharmacol ; 454: 116249, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36126765

RESUMO

Hainanolide (HN) is a norditerpenoid metabolite extract from Cephalotaxus fortunei Hook. f. C. fortunei Hook. f. is renowned for the active alkaloids, such as harringtonine (HT) and homoharringtonin (HTT), which have been clinically used to treat chronic myeloid leukemia. Nowadays, diterpenoids, another important metabolite, attracted the attention of chemists. Among them, Hainanolide (HN), a cephalotane-type diterpenoid, has been proven to possess potent antitumor activities. However, the underlying therapeutic mechanisms of HN in anti-tumor have not been investigated yet. Our present study demonstrated that HN inhibited HCT-116 and HCT-15 cell proliferation in a dose- and time-dependent manner. Further studies demonstrated that HN can induce G2/M phase arrest and alter the Cdc25C/Cdc2/CyclinB1 proteins. Western blot indicated that HN promoted apoptosis by up-regulating Bax and down-regulated Bcl-2. And the caspase-3 and caspase-9 activities of HCT-116 and HCT-15 cells were increased. Transcriptome analysis is used to reveal the possible mechanism. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested the genes were mainly enriched in the MAPK signaling pathway. Certainly, HN activates MAPK signaling pathway. In vivo, HN prevented the AOM/DSS-induced tumorigenesis of colon cancer in C57BL/6 mice. Our study indicated that HN inhibits the progression of colon cancer cells by blocking the cell cycle, inducing apoptosis, and activating the MAPK pathway. This study provides a theoretical and experimental scientific basis for future investigations of the antitumor effects of HN against colon cancer.


Assuntos
Neoplasias do Colo , Diterpenos , Harringtoninas , Animais , Apoptose , Caspase 3/metabolismo , Caspase 9/metabolismo , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/metabolismo , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Harringtoninas/farmacologia , Harringtoninas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Proteína X Associada a bcl-2/metabolismo
17.
Int J Mol Sci ; 23(18)2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36142859

RESUMO

Although the impacts of Saccharomyces cerevisiae on cancers are mentioned, data on its use in mice with cyclic GMP-AMP synthase deficiency (cGAS-/-) are even rarer. Here, 12 weeks of oral administration of S. cerevisiae protected cGAS-/- mice from azoxymethane (AOM)-induced colon cancers, partly through dysbiosis attenuation (fecal microbiome analysis). In parallel, a daily intralesional injection of a whole glucan particle (WGP; the beta-glucan extracted from S. cerevisiae) attenuated the growth of subcutaneous tumor using MC38 (murine colon cancer cell line) in cGAS-/- mice. Interestingly, the incubation of fluorescent-stained MC38 with several subtypes of macrophages, including M1 (using Lipopolysaccharide; LPS), M2 (IL-4), and tumor-associated macrophages (TAM; using MC38 supernatant activation), could not further reduce the tumor burdens (fluorescent intensity) compared with M0 (control culture media). However, WGP enhanced tumoricidal activities (fluorescent intensity), the genes of M1 pro-inflammatory macrophage polarization (IL-1ß and iNOS), and Dectin-1 expression and increased cell energy status (extracellular flux analysis) in M0, M2, and TAM. In M1, WGP could not increase tumoricidal activities, Dectin-1, and glycolysis activity, despite the upregulated IL-1ß. In conclusion, S. cerevisiae inhibited the growth of colon cancers through dysbiosis attenuation and macrophage energy activation, partly through Dectin-1 stimulation. Our data support the use of S. cerevisiae for colon cancer protection.


Assuntos
Neoplasias do Colo , beta-Glucanas , Animais , Azoximetano , Neoplasias do Colo/metabolismo , Meios de Cultura/metabolismo , Disbiose/metabolismo , Interleucina-4/metabolismo , Lectinas Tipo C , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Camundongos , Nucleotidiltransferases/metabolismo , Saccharomyces cerevisiae/metabolismo , beta-Glucanas/metabolismo , beta-Glucanas/farmacologia
18.
Molecules ; 27(17)2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36080457

RESUMO

To improve the antitumor effect of combined capecitabine (CAP) and osimertinib (OSI) therapy and quickly and efficiently reduce tumor volumes for preoperative chemotherapy, we designed a compound CAP colon-targeted microparticle (COPMP) prepared by coaxial electrospray. COPMP is a core-shell microparticle composed of a Eudragit S100 outer layer and a CAP/OSI-loaded PLGA core. In this study, we characterized its size distribution, drug loading (DL), encapsulation efficiency (EE), differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, formula ratio, cellular growth inhibition, and in vivo antitumor efficacy. COPMP is of spherical appearance with a size of 1.87 ± 0.23 µm. The DLs of CAP and OSI are 4.93% and 4.95%, respectively. The DSC showed that the phase state of CAP and OSI changed after encapsulation. The FTIR results indicated good compatibility between the drug and excipients. The release curve showed that CAP and OSI were released in a certain ratio. They were barely released prior to 2 h (pH 1.0), less than 50% was released between 3 and 5 h (pH 6.8), and sustained release of up to 80% occurred between 6 and 48 h (pH 7.4). CAP and OSI demonstrated a synergistic effect on HCT-116 cells. In a colon tumor model, the tumor inhibition rate after oral administration of COPMP reached 94% within one week. All the data suggested that COPMP promotes the sustained release of CAP and OSI in the colon, which provides a preoperative chemotherapy scheme for the treatment of colon cancer.


Assuntos
Colo , Neoplasias do Colo , Capecitabina/química , Capecitabina/farmacologia , Colo/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Humanos , Tamanho da Partícula
19.
J Tradit Chin Med ; 42(5): 701-706, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36083476

RESUMO

OBJECTIVE: To observe the anticancer effects of the granular preparation of Tenglong Buzhong decoction (,TBD), i.e Tenglong Buzhong granules (, TBG), in human SW620 colon cancer. METHODS: BALB/c nude mice were subcutaneously transplanted with SW620 cells, and treated with TBG (2.56 g/kg, once per day) and/or 5-Fu (104 mg/kg, once per week) for 21 d. Apoptosis, Caspase activities and cellular senescence were measured by commercial kits. The protein expression and phosphorylation were detected by Western blot or immunohistochemistry. RESULTS: TBG and 5-Fu inhibited tumor growth. The tumor inhibition rate of the TBG, 5-Fu, and TBG+5-Fu groups was 42.25%, 51.58%, and 76.08%, respectively. Combination of TBG and 5-Fu showed synergetic anti-cancer effects. TBG and 5-Fu induced apoptosis, activated caspase-3, -8, and -9, increased SMAC expression, inhibited XIAP expression. TBG induced cellular senescence, upregulated cyclin-dependent kinase inhibitor 1a (CDKN1a) and cyclin-dependent kinase inhibitor 2a (CDKN2a) expression, and inhibited phosphorylation of retinoblastoma-associated protein (RB) and expression of cyclin E1 (CCNE1) and cyclin-dependent kinases (CDK) 2. TBG also inhibited angiogenesis accompanied by downregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α). CONCLUSIONS: TBG inhibits SW620 colon cancer growth, induces apoptosis SMAC-XIAP-Caspases signaling, induces cellular senescence through CDKN1a/CDKN2a-RB-E2F signaling, inhibits angiogenesis by down-regulation of HIF-1α and VEGF, and enhances the effects of 5-Fu.


Assuntos
Neoplasias do Colo , Fator A de Crescimento do Endotélio Vascular , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Quinases Ciclina-Dependentes , Ciclinas , Fluoruracila , Humanos , Camundongos , Camundongos Nus , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Front Immunol ; 13: 932412, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36045676

RESUMO

Immune cells and the cytokines they produce are important mediators of the transition from colitis to colon cancer, but the mechanisms mediating this disease progression are poorly understood. Interferon gamma (IFN-γ) is known to contribute to the pathogenesis of colitis through immune modulatory mechanisms, and through direct effects on endothelial and epithelial homeostasis. Here we explore whether IFN-γ influences tumor progression by expanding the effector memory T cells (TEM) population and restricting the expression of tumor suppressors in a preclinical model of spontaneous colitis-associated colorectal cancer (CAC). We show that IFN-γ expression is significantly increased both in the T cells and the colonic mucosal epithelia of mice with a T cell-restricted deletion of the TGF-ß intermediate, SMAD4 (Smad4TKO). The increase of IFN-γ expression correlates with the onset of spontaneous CAC in Smad4TKO mice by 6 months of age. This phenotype is greatly ameliorated by the introduction of a germline deletion of IFN-γ in Smad4TKO mice (Smad4TKO/IFN-γKO, DKO). DKO mice had a significantly reduced incidence and progression of CAC, and a decrease in the number of mucosal CD4+ TEM cells, when compared to those of Smad4TKO mice. Similarly, the colon epithelia of DKO mice exhibited a non-oncogenic signature with a decrease in the expression of iNOS and p-STAT1, and a restoration of the tumor suppressor gene, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In vitro, treatment of human colon cancer cells with IFN-γ decreased the expression of 15-PGDH. Our data suggest that Smad4-deficient T cells promote CAC through mechanisms that include an IFN-γ-dependent suppression of the tumor suppressor 15-PGDH.


Assuntos
Neoplasias Associadas a Colite , Neoplasias do Colo , Hidroxiprostaglandina Desidrogenases/metabolismo , Interferon gama/metabolismo , Proteína Smad4/metabolismo , Animais , Colite , Neoplasias Associadas a Colite/metabolismo , Neoplasias Associadas a Colite/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Interferon gama/genética , Camundongos , Proteína Smad4/genética , Linfócitos T/metabolismo
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