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1.
Int J Biol Sci ; 16(7): 1194-1206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32174794

RESUMO

Metabolic reprogramming is a hallmark of cancer. Mammalian genome is characterized by pervasive transcription, generating abundant non-coding RNAs (ncRNAs). Long non-coding RNAs (lncRNAs) are freshly discovered functional ncRNAs exerting extensive regulatory impact through diverse mechanisms. Emerging studies have revealed widespread roles of lncRNAs in the regulation of various cellular activities, including metabolic pathways. In this review, we summarize the latest advances regarding the regulatory roles of lncRNAs in cancer metabolism, particularly their roles in mitochondrial function, glucose, glutamine, and lipid metabolism. Moreover, we discuss the clinical application and challenges of targeting lncRNAs in cancer metabolism. Understanding the complex and special behavior of lncRNAs will allow a better depiction of cancer metabolic networks and permit the development of lncRNA-based clinical therapies by targeting cancer metabolism.

2.
Sci Rep ; 10(1): 560, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953417

RESUMO

The aim of current study was to use competing risk model to assess whether medullary carcinoma of the breast (MCB) has a better prognosis than invasive ductal carcinomas of breast cancer (IDC), and to build a competing risk nomogram for predicting the risk of death of MCB. We involved 3,580 MCB patients and 319,566 IDC patients from Surveillance, Epidemiology, and End Results (SEER) database. IDC was found to have a worse BCSS than MCB (Hazard ratio (HR) > 1, p < 0.001). The 5-year cumulative incidences of death (CID) was higher in IDC than MCB (p < 0.001). Larger tumor size, increasing number of positive lymph nodes and unmarried status were found to worsen the BCSS of MCB (HR > 1, p < 0.001). We found no association between ER, PR, radiotherapy or chemotherapy and MCB prognosis (p > 0.05). After a penalized variable selection process, the SH model-based nomogram showed moderate accuracy of prediction by internal validation of discrimination and calibration with 1,000 bootstraps. In summary, MCB patients had a better prognosis than IDC patients. Interestingly, unmarried status in addition to expected risk factors such as larger tumor size and increasing number of positive lymph nodes were found to worsen the BCSS of MCB. We also established a competing risk nomogram as an easy-to-use tool for prognostic estimation of MCB patients.

3.
Epigenomics ; 12(1): 19-36, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31833403

RESUMO

Aim: To identify methylation-associated genes in the carcinogenesis of colorectal cancer (CRC). Materials & methods: Genome-wide patterns of DNA methylation and gene expression in CRC tissues and adjacent normal tissues were determined and further validated in The Cancer Genome Atlas data and Chinese CRC patients, respectively. Gene overexpression and knockdown cells were constructed to investigate their biological roles in CRC. Results: After validations, hypermethylation of eight genes were found to be correlated with their reduced transcription, and hypomethyaltion of three genes were associated with their upregulation. CADM3, CNRIP1, GRHL2, GRIA4, GSTM2 and NRXN1 were associated with the overall survival of CRC patients. CNRIP1 and GSTM2 were mainly responsible for the proliferation in CRC cells. Conclusion: A total of 11 genes may be promising biomarkers for CRC.

4.
Gut ; 69(2): 365-379, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31076403

RESUMO

OBJECTIVE: Hepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy. DESIGN: Functional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined. RESULTS: Accumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model. CONCLUSION: Our results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.


Assuntos
Carcinoma Hepatocelular/terapia , Imunoterapia/métodos , Neoplasias Hepáticas/terapia , Animais , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/imunologia , Reprogramação Celular/imunologia , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Células Estreladas do Fígado/imunologia , Humanos , Tolerância Imunológica , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/terapia , Masculino , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Células Supressoras Mieloides/imunologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas , Microambiente Tumoral , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
5.
Oncol Lett ; 18(6): 6594-6604, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31807175

RESUMO

The aim of the present study was to use a competing risk model to analyze the prognostic value of mucinous adenocarcinoma (MAC) in patients with colorectal cancer (CRC). An additional aim was to construct nomograms for estimating the 3- and 5-year overall survival (OS) and cancer specific survival (CSS) rates of patients with primary CRC with MAC. The data were extracted from the Surveillance, Epidemiology, and End Results database, and a Multivariate Cox model and competing risk model were applied to assess the OS and CSS. Cox-based and competing risk-based nomograms were constructed and internally validated by discrimination and calibration, using the bootstrapping method with 1,000 times replicates. A total of 13,035 MAC and 61,958 non-mucinous adenocarcinoma (NMAC) CRC patients were enrolled in the present study. Compared with NMAC, MAC patients had a poorer OS and CSS time in the overall population, and in subgroups that comprised metastatic, non-metastatic, male, site of sigmoid colon, rectosigmoid junction and rectal CRC cases (HR>1; P<0.05). The Cox and competing risk-based nomograms showed effective discrimination and calibration. In conclusion, MAC was associated with poor OS and CSS in patients with CRC of the distal colon and rectum. The nomograms of primary CRC patients with MAC may aid the identification of individual patients with a high risk of overall mortality and cancer-associated mortality within 3 or 5 years.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31637005

RESUMO

Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) greatly improved clinical outcomes of patients with non-small cell lung cancer (NSCLC). Unfortunately, primary and acquired resistance limits their clinical benefits. To overcome such resistance, new generations of EGFR TKIs have been developed by targeting newly identified mutations in EGFR. However, much less effort has been put into alternative strategies, such as targeting the intrinsic protective responses to EGFR TKIs. In this study, we found that EGFR TKIs, including gefitinib and AZD9291, impaired lysosome-dependent degradation of SQSTM1, thus compromising their anti-cancer efficiency. By accumulating in the lysosome lumen, gefitinib and AZD9291 attenuated lysosomal acidification and impaired autolysosomal degradation of SQSTM1 owing to their intrinsic alkalinity. As a result, SQSTM1 protein was stabilized in response to gefitinib and AZD9291 treatment and conferred EGFR TKI resistance. Depleting SQSTM1 significantly increased the sensitivity of NSCLC cells to gefitinib and AZD9291 both in vitro and in vivo. Furthermore, a chemically modified gefitinib analog lacking alkalinity displayed stronger inhibitory effects on NSCLC cells. Therefore, targeting accumulated SQSTM1 or chemically modified EGFR TKIs may represent new strategies to increase the effectiveness of EGFR targeted therapy.

7.
PeerJ ; 7: e7252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309004

RESUMO

Background: The aim of current study was to use competing risk model to calculate the potential differences that age played in the prognosis of different breast cancer subtypes. Methods: The cohort was selected from Surveillance, Epidemiology, and End Results (SEER) program. The cumulative incidences of death (CID) was assessed for breast cancer caused deaths and other causes of mortality. The multivariate Cox proportional hazards regression model and the multivariate subdistribution hazard (SH) model were used to evaluate the prognostic value of age in different breast cancer subtypes. Results: We involved 33,968 breast cancer patients into our cohort. We found older patients had worse overall survival (OS) than young patients in hormone receptor positive and human epidermal growth factor receptor 2 positive breast cancer (HR+/HER2+) (≥40 vs. <40, HR = 2.07, 95% CI [1.28-3.35], p < 0.05). However, when we used competing risk model, we found young age was an independent risk factor only for triple negative breast cancer (TNBC) (≥40 vs. <40, HR = 0.71, 95% CI [0.56-0.89], p < 0.05). No association was found in other groups. Conclusion: Our research was currently the largest sample size study and the first competing risk model-based study on the prognostic association between age and different breast cancer subtypes. We found <40 years patients had worse breast cancer specific survival (BCSS) than older patients in the TNBC subtype.

8.
Front Oncol ; 9: 578, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31334112

RESUMO

Polygonum perfoliatum L. belongs to the genus Polygonaceae and has a long history to be used as a Chinese medicinal herb to reduce swelling, control body temperature, and promote detoxification. However, its anticancer activity and mechanisms of action have not been evaluated yet. In the present study, we used several cell lines and xenograft models from different cancers to demonstrate the broad-spectrum anticancer activity of P. perfoliatum L as well as its underlying mechanisms of action in vitro and in vivo. The ethyl acetate extract of P. perfoliatum L showed good anticancer activity and was further fractioned to obtain five active components, including PEA to PEE. Among these fractions, PEC showed the strongest cytotoxicities against various cancer cell lines. It was further observed that PEC inhibited cancer cell growth, arrested cells at G2 phase, and induced apoptosis in vitro and suppressed tumor growth and angiogenesis in vivo in a dose- and time-dependent manner. Furthermore, PEC decreased the expression of vascular endothelial growth factor (VEGF) and micro-vascular density (MVD) in tumor tissues in vivo. It also promoted the proliferation of T and B lymphocytes, increased the activities of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), enhanced the secretion of interleukin 2 (IL-2) by spleen cells, and raised the levels of IgG, IgG2a, and IgG2b antibodies in tumor-bearing mice in vivo, which were at least partially responsible for the anticancer activity of PEC. In summary, PEC has shown broad-spectrum anticancer activities without causing any host toxicity in vitro and in vivo and may be developed as a preventive and therapeutic agent against human cancer. Further studies are urgently needed to determine the anticancer compounds in PEC and their detailed molecular mechanisms.

9.
Oncogene ; 38(36): 6370-6381, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31312020

RESUMO

Inactivation of the tumor suppressor NF2/merlin underlies neurofibromatosis type 2 (NF2) and some sporadic tumors. Previous studies have established that merlin mediates contact inhibition of proliferation; however, the exact mechanisms remain obscure and multiple pathways have been implicated. We have previously reported that merlin inhibits Ras and Rac activity during contact inhibition, but how merlin regulates Ras activity has remained elusive. Here we demonstrate that merlin can directly interact with both Ras and p120RasGAP (also named RasGAP). While merlin does not increase the catalytic activity of RasGAP, the interactions with Ras and RasGAP may fine-tune Ras signaling. In vivo, loss of RasGAP in Schwann cells, unlike the loss of merlin, failed to promote tumorigenic growth in an orthotopic model. Therefore, modulation of Ras signaling through RasGAP likely contributes to, but is not sufficient to account for, merlin's tumor suppressor activity. Our study provides new insight into the mechanisms of merlin-dependent Ras regulation and may have additional implications for merlin-dependent regulation of other small GTPases.


Assuntos
Neurofibromina 2/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , Células Cultivadas , Proteínas Ativadoras de GTPase/metabolismo , Genes Supressores de Tumor , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neurofibromatose 2/genética , Neurofibromatose 2/metabolismo , Neurofibromina 2/metabolismo , Ligação Proteica , Transdução de Sinais/genética
10.
Theranostics ; 9(10): 2999-3013, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244938

RESUMO

Background & Aims: Dysregulation of metabolism plays an important role in the development and progression of cancers, while the underlying mechanisms remain largely unknown. This study aims to explore the regulation and relevance of glycolysis in chemoresistance of gastric cancer. Methods: Biochemical differences between chemoresistant and chemosensitive cancer cells were determined by metabolism profiling, microarray gene expression, PCR or western blotting. Cancer cell growth in vitro or in vivo were analyzed by viability, apoptosis and nude mice assay. Immunoprecipation was used to explore the interaction of proteins with other proteins or DNAs. Results: By metabolic and gene expression profiling, we found that pyruvate dehydrogenase kinase 3 (PDK3) was highly expressed to promote glycolysis in chemoresistant cancer cells. Its genetic or chemical inhibition reverted chemoresistance in vitro and in vivo. It was transcriptionally regulated by transcription factor HSF1 (Heat shock factor 1). Interestingly, PDK3 can localize in the nucleus and interact with HSF1 to disrupt its phosphorylation by GSK3ß. Since HSF1 was subjected to FBXW7-catalyzed polyubiquitination in a phosphorylation-dependent manner, PDK3 prevented HSF1 from proteasomal degradation. Thus, metabolic enzyme PDK3 and transcription factor HSF1 forms a positive feedback loop to promote glycolysis. As a result, inhibition of HSF1 impaired enhanced glycolysis and reverted chemoresistance both in vitro and in vivo. Conclusions: PDK3 forms a positive feedback loop with HSF1 to drive glycolysis in chemoresistance. Targeting this mitonuclear communication may represent a novel approach to overcome chemoresistance.

11.
PLoS One ; 14(6): e0218338, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31194837

RESUMO

Gastric cancer is a leading cause of cancer worldwide. Our previous studies showed that aberrant activation of JAK/STAT3 signaling confer epigenetically silences STAT3 target genes in gastric cancer. To further investigate the clinical significance of this phenomenon, we performed Illumina 850K methylation microarray analysis in AGS gastric cancer cells, and cells depleted of STAT3. Integrative computational analysis identified SPG20 as a putative STAT3 epigenetic target, showing promoter hypomethylation in STAT3-depleted AGS cells. Bisulphite pyrosequencing and qRT-PCR confirmed that SPG20 is epigenetically silenced by promoter hypermethylation in a panel of gastric cancer cell lines including AGS cells, but not in immortalized gastric epithelial GES cells. Expression of SPG20 could be restored by the treatment with a DNMT inhibitor, further suggesting that SPG20 is epigenetically silenced by promoter methylation. Clinically, a progressive increase in SPG20 methylation was observed in tissues samples from gastritis (n = 34), to intestinal metaplasia (IM, n = 33), to gastric cancer (n = 53). Importantly, SPG20 methylation could be detected in cell-free DNA isolated from serum samples of gastritis, IM and gastric cancer patients, having a progressive similar to tissues. Taken together, SPG20, a potential STAT3 target, is frequently methylated in gastric cancer, representing a novel noninvasive biomarker for early detection of this deadly disease.


Assuntos
Proteínas de Ciclo Celular/genética , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Neoplasias Gástricas/diagnóstico
12.
Cell Death Dis ; 10(5): 363, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043584

RESUMO

Chemoresistance is one of the most important challenges in the clinical management of lung cancer. SIRT1 is a NAD dependent protein deacetylase and implicated in diverse cellular processes such as DNA damage repair, and cancer progression. SIRT1 is upregulated in chemoresistant lung cancer cells, genetic knockdown or chemical inhibition of SIRT1 reversed chemoresistance by enhancing DNA damage and apoptosis activation, accompanied with XRCC1 degradation. E3 ligase ß-TrCP catalyzed the poly-ubiquitination of XRCC1 to promote its proteasome-dependent degradation. SIRT1 bound and deacetylated XRCC1 at lysine K260, K298 and K431, preventing it from ß-TrCP-dependent ubiquitination. Mutations of these three lysine sites in XRCC1 abrogated the interaction with ß-TrCP and prolonged the half-life of XRCC1 protein. Here, we describes SIRT1 confers chemoresistance to lung cancer cells by deacetylating and stabilizing XRCC1. Therefore, targeting SIRT1 might be a new strategy to manage the chemoresistance of lung cancer, and probably other cancers.

13.
Cell Death Dis ; 10(6): 383, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097692

RESUMO

Chemoresistance remains the uppermost disincentive for cancer treatment on account of many genetic and epigenetic alterations. Long non-coding RNAs (lncRNAs) are emerging players in promoting cancer initiation and progression. However, the regulation and function in chemoresistance are largely unknown. Herein, we identified ARHGAP5-AS1 as a lncRNA upregulated in chemoresistant gastric cancer cells and its knockdown reversed chemoresistance. Meanwhile, high ARHGAP5-AS1 expression was associated with poor prognosis of gastric cancer patients. Intriguingly, its abundance is affected by autophagy and SQSTM1 is responsible for transporting ARHGAP5-AS1 to autophagosomes. Inhibition of autophagy in chemoresistant cells, thus, resulted in the upregulation of ARHGAP5-AS1. In turn, it activated the transcription of ARHGAP5 in the nucleus by directly interacting with ARHGAP5 promoter. Interestingly, ARHGAP5-AS1 also stabilized ARHGAP5 mRNA in the cytoplasm by recruiting METTL3 to stimulate m6A modification of ARHGAP5 mRNA. As a result, ARHGAP5 was upregulated to promote chemoresistance and its upregulation was also associated with poor prognosis in gastric cancer. In summary, impaired autophagic degradation of lncRNA ARHGAP5-AS1 in chemoresistant cancer cells promoted chemoresistance. It can activate the transcription of ARHGAP5 in the nucleus and stimulate m6A modification of ARHGAP5 mRNA to stabilize ARHGAP5 mRNA in the cytoplasm by recruiting METTL3. Therefore, targeting ARHGAP5-AS1/ARHGAP5 axis might be a promising strategy to overcome chemoresistance in gastric cancer.

14.
Cell Death Dis ; 10(4): 270, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894512

RESUMO

Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer with the absence of targeted therapy, resulting in poor prognosis in patients. Chemotherapy remains the mainstay of treatment for TNBC; however, development of drug resistance is the main obstacle for successful treatments. In recent years, long non-coding RNA (lncRNA) has been implicated in multiple biological functions in various diseases, particularly cancers. Accumulating evidence suggested that lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) expression is dysregulated in many human cancers and thus is a useful prognostic marker for cancer patients. Nevertheless, the mechanism of how NEAT1 confers drug resistance in TNBC is still largely unknown. We performed lncRNA profiling by the LncRNA Profiler qPCR Array Kit in normal control (NC) and breast cancers (BC) blood samples and further validated in a larger cohort of samples by qRT-PCR. Gene expression level and localization were investigated by qRT-PCR, western blotting, and immunofluorescence staining. Flow cytometric analysis was carried out to detect cancer stem cells. Functional studies were performed both in vitro and in vivo xenograft model. Among 90 lncRNAs, NEAT1 was highly expressed in the blood samples of breast cancer patients than in NC. In particular, the expression of NEAT1 was higher in TNBC tissues than other subgroups. Functional studies revealed that NEAT1 conferred oncogenic role by regulating apoptosis and cell cycle progression in TNBC cells. We identified that knockdown of NEAT1 sensitized cells to chemotherapy, indicating the involvement in chemoresistance. Importantly, shNEAT1 reduced stem cell populations such as CD44+/CD24-, ALDH+, and SOX2+, implicating that NEAT1 was closely related to cancer stemness in TNBC. Our data highlighted the roles of NEAT1 chemoresistance and cancer stemness, suggesting that it could be used as a new clinical therapeutic target for treating TNBC patients especially those with drug resistance.

15.
J Cancer ; 10(4): 949-956, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30854101

RESUMO

Background: Chromosomally unstable tumors account for 50% of gastric cancer. CHFR plays a role in controlling chromosomal instability and its inactivation will eventually lead to tumorigenesis. In addition to genetic deletion, DNA methylation could silence the expression of many cancer-related genes including CHFR. Its methylation was found to be associated with the initiation and progression of gastric cancer. Methods: We performed a meta-analysis involving methylation analyses of CHFR promoter in gastric cancer. Nineteen studies with 1,249 tumor tissues and 745 normal tissues had been included in current study. Results: We found that CHFR methylation was significantly higher in gastric cancer (studies numbers = 15, cases/controls = 862/745, odds ratio (OR) = 7.46, 95% confidence index (95% CI) = 4.99-11.14). Methylation array data was also obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas network (TCGA). There were 7 out of 13 CHFR methylation probes target to the same CpG island region (hg19, 131973620-131975130) showed the CHFR methylation was higher in gastric cancers than normal controls. Eight probes showed CHFR promoter hypermethylation was associated with longer overall survival of gastric cancer patients (Hazard Ratio < 1). Conclusions: The CHFR promoter hypermethylation was associated with gastric cancer and played a protective role in gastric cancer process. Its methylation could be a potential biomarker for the diagnosis and prognosis of gastric cancer.

16.
JCI Insight ; 4(4)2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30668548

RESUMO

Abnormal activation of neddylation modification and dysregulated energy metabolism are frequently seen in many types of cancer cells. Whether and how neddylation modification affects cellular metabolism remains largely unknown. Here, we showed that MLN4924, a small-molecule inhibitor of neddylation modification, induces mitochondrial fission-to-fusion conversion in breast cancer cells via inhibiting ubiquitylation and degradation of fusion-promoting protein mitofusin 1 (MFN1) by SCFß-TrCP E3 ligase and blocking the mitochondrial translocation of fusion-inhibiting protein DRP1. Importantly, MLN4924-induced mitochondrial fusion is independent of cell cycle progression, but confers cellular survival. Mass-spectrometry-based metabolic profiling and mitochondrial functional assays reveal that MLN4924 inhibits the TCA cycle but promotes mitochondrial OXPHOS. MLN4924 also increases glycolysis by activating PKM2 via promoting its tetramerization. Biologically, MLN4924 coupled with the OXPHOS inhibitor metformin, or the glycolysis inhibitor shikonin, significantly inhibits cancer cell growth both in vitro and in vivo. Together, our study links neddylation modification and energy metabolism, and provides sound strategies for effective combined cancer therapies.

17.
J Ethnopharmacol ; 232: 47-54, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30552993

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The development of a multidrug-resistant (MDR) phenotype is a main obstacle to the successful treatment of breast cancer. Saponins of several herbs are considered as promising candidates for drug resistance treatment. We extracted Paris saponin VII (PS VII) from Trillium tschonoskii Maxim. and investigated whether it could sensitize chemoresistant breast cancer cells MCF-7/ADR to the cytotoxic effects of adriamycin. MATERIALS AND METHODS: MCF-7/ADR cells were exposed to 0.5 µM PSVII plus different concentrations of adriamycin (0-100 µM). Then, MTT assay and adriamycin accumulation assay were used to assess cell proliferation and intracellular adriamycin retention. P glycoprotein levels and intracellular rhodamine 123 (Rh-123) accumulations were investigated to measure the expression and activity of P-glycoprotein. A xenograft model of nude mouse was utilized to observe the effect of PSVII in vivo. RESULTS: Treatment with PSVII influenced cell viability of MCF-7/ADR cells, as well as sensitized MCF-7/ADR cells to the cytotoxic effects of adriamycin. Moreover, PSVII significantly downregulated MDR1 expression in MCF-7/ADR cells. Intravenous administration of PSVII significantly enhanced anticancer efficacy of adriamycin to MCF-7/ADR xenograft model in nude mice. CONCLUSION: These findings suggested a possible application of PSVII in combination with chemotherapy and/or as neo-adjuvant therapy in the treatment of MDR breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Saponinas/farmacologia , Saponinas/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Doxorrubicina/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Fitoterapia , Trillium , Carga Tumoral/efeitos dos fármacos
18.
Am J Cancer Res ; 8(11): 2210-2226, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555739

RESUMO

Extracellular vesicles (EVs), named as exosomes, were recently found to play important roles in cell-cell communication by transducing various biochemical and genetic information. Exosomes, secreted from either tumor cells or stromal cells including immune cells, can eventually remodel tumor environment to promote tumor progression such as metastasis and multidrug resistance (MDR). Therefore, the detection or targeting of biochemical and genetic cargos like proteins, lipids, metabolites and various types of RNAs or DNAs are believed to be valuable for the diagnosis and treatment of human cancer. In this review, we will summarize recent progresses in the research of exosomes especially its biological and clinical relevance to MDR. By doing so, we hope it could be valuable for the prevention, detection and intervention of MDR which is one of the major challenges for the clinical management of human cancers.

19.
Cell Death Dis ; 9(9): 905, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185773

RESUMO

Foxp3+ regulatory T cells (Tregs) can inhibit immune responses and maintain immune tolerance by secreting immunosuppressive TGF-ß1 and IL-10. However, the efficiency of Tregs become the major obstacle to their use for immunotherapy. In this study, we investigated the relevance of the C-type lectin receptor CD69 to the suppressive function. Compared to CD4+Foxp3+CD69- Tregs (CD69- Tregs), CD4+Foxp3+CD69+ Tregs (CD69+ Tregs) displayed stronger ability to maintain immune tolerance. CD69+ Tregs expressed higher levels of suppression-associated markers such as CTLA-4, ICOS, CD38 and GITR, and secreted higher levels of IL-10 but not TGF-ß1. CD69+ Tregs from Il10+/+ rather than Il10-/- mice significantly inhibit the proliferation of CD4+ T cells. CD69 over-expression stimulated higher levels of IL-10 and c-Maf expression, which was compromised by silencing of STAT3 or STAT5. In addition, the direct interaction of STAT3 with the c-Maf promoter was detected in cells with CD69 over-expression. Moreover, adoptive transfer of CD69+ Tregs but not CD69-Tregs or CD69+ Tregs deficient in IL-10 dramatically prevented the development of inflammatory bowel disease (IBD) in mice. Taken together, CD69 is important to the suppressive function of Tregs by promoting IL-10 production. CD69+ Tregs have the potential to develop new therapeutic approach for autoimmune diseases like IBD.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Colite/imunologia , Tolerância Imunológica/imunologia , Interleucina-10/imunologia , Lectinas Tipo C/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva/métodos , Animais , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/imunologia , Proliferação de Células/fisiologia , Feminino , Doenças Inflamatórias Intestinais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT5/imunologia , Fator de Crescimento Transformador beta1/imunologia
20.
Am J Cancer Res ; 8(8): 1576-1585, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210925

RESUMO

Triple-negative breast cancer (TNBC) represents around 15%-20% of newly diagnosed breast cancer and is more aggressive than other breast cancer sub-types. Infiltrating duct carcinoma (IDC) is the most common type of TNBC. Nomogram is a valuable tool for prognosis prediction by integrating different biological and clinical variables. The purpose of current study was to evaluate the prognostic value of clinical factors of TNBC patients with IDC histology type and construct nomograms for their outcome prediction. The cohort was selected from Surveillance, Epidemiology, and End Results (SEER) program. Univariate and multivariate analyses were performed using Cox proportional hazards regression model to evaluate the prognostic value of involved variables. Nomogram was constructed from the multivariate logistic regression model to combine all the prognostic factors to predict the 1-year and 3-year prognosis of TNBC patients with histology of IDC. Internal validation of nomogram was tested by discrimination and calibration. We identified 14,538 patients with the median and max survival time was 28 months and 59 months, respectively. There were 1,592 deaths, accounting for 10.9% of the cohort. Multivariate analyses showed that grade, tumor stage, tumor size, regional nodes positive, marital status, experience of radiotherapy or chemotherapy were independent prognostic factors of IDC of TNBC. Eleven variables were combined to construct 1-year and 3-year nomograms. It was revealed that the C-index of the nomograms was 0.763 and the calibration curves showed good agreement between the nomogram prediction and actual observation. Current study was the first one to construct nomograms of TNBC patients with IDC histology, which could help physicians to identify patients at high risk for intensive treatment or follow-up.

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