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1.
Cancer Res ; 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35507004

RESUMO

N6-methyladenosine (m6A) methylation is an abundant modification in eukaryotic mRNAs. Accumulating evidence suggests a role for RNA m6A methylation in various aspects of cancer biology. In this study, we aimed to explore the biological role of RNA m6A modification in tumor metastasis and to identify novel therapeutic strategies for esophageal squamous cell carcinoma (ESCC). Integration of genome-wide CRISPR/Cas9 functional screening with highly invasive and metastatic ESCC subline models led to the identification of METTL3, the catalytic subunit of the N6-adenosine-methyltransferase complex, as a promoter of cancer metastasis. METTL3 expression was upregulated in ESCC tumors and metastatic tissues. In vitro and in vivo experiments indicated that METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. Investigation into regulation of METTL3 expression found that KAT2A increased H3K27 acetylation levels in the METTL3 promoter region and activated transcription of METTL3 while SIRT2 exerted the opposite effects. Molecular docking and computational screening in a Food and Drug Administration (FDA)-approved compound library consisting of 1,443 small molecules identified compounds targeting METTL3 to suppress cancer metastasis. Elvitegravir, originally developed to treat human immunodeficiency virus (HIV) infection, suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation. Overall, RNA m6A modifications are important in cancer metastasis, and targeting METTL3 with elvitegravir has therapeutic potential for treating ESCC.

3.
MedComm (2020) ; 2(3): 315-340, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34766149

RESUMO

Cancer is a leading cause of death worldwide. Surgery is the primary treatment approach for cancer, but the survival rate is very low due to the rapid progression of the disease and presence of local and distant metastasis at diagnosis. Adjuvant chemotherapy and radiotherapy are important components of the multidisciplinary approaches for cancer treatment. However, resistance to radiotherapy and chemotherapy may result in treatment failure or even cancer recurrence. Radioresistance in cancer is often caused by the repair response to radiation-induced DNA damage, cell cycle dysregulation, cancer stem cells (CSCs) resilience, and epithelial-mesenchymal transition (EMT). Understanding the molecular alterations that lead to radioresistance may provide new diagnostic markers and therapeutic targets to improve radiotherapy efficacy. Patients who develop resistance to chemotherapy drugs cannot benefit from the cytotoxicity induced by the prescribed drug and will likely have a poor outcome with these treatments. Chemotherapy often shows a low response rate due to various drug resistance mechanisms. This review focuses on the molecular mechanisms of radioresistance and chemoresistance in cancer and discusses recent developments in therapeutic strategies targeting chemoradiotherapy resistance to improve treatment outcomes.

4.
MedComm (2020) ; 2(3): 453-466, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34766155

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies currently. Despite advances in drug development, the survival and response rates in CRC patients are still poor. In our previous study, a library comprised of 1056 bioactive compounds was used for screening of drugs that could suppress CRC. Lomerizine 2HCl, which is an approved prophylactic drug for migraines, was selected for our studies. The results of in vitro and in vivo assays suggested that lomerizine 2HCl suppresses cell growth and promotes apoptosis in CRC cells. Moreover, lomerizine 2HCl inhibits cell migration and invasion of CRC. RNA sequencing analysis and Western blotting confirmed that lomerizine 2HCl can inhibit cell growth, migration, and invasion through PI3K/AKT/mTOR signaling pathway and induces protective autophagy in CRC. Meanwhile, autophagy inhibition by 3-methyladenine (3-MA) increases lomerizine 2HCl-induced cell apoptosis. Taken together, these results imply that lomerizine 2HCl is a potential anticancer agent, and the combination of lomerizine 2HCl and autophagy inhibitors may serve as a novel strategy to increase the antitumor efficacy of agents in the treatment of CRC.

6.
Adv Sci (Weinh) ; 7(16): 2000925, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32832354

RESUMO

Metastasis accounts for 90% of cancer death worldwide, and effective therapeutic strategies are lacking. The aim of this work is to identify the key drivers in tumor metastasis and screen therapeutics for treatment of esophageal squamous cell carcinoma (ESCC). Gene Ontology analysis of The Cancer Genome Atlas (TCGA) gene expression datasets of ESCC patients with or without lympy metastasis identifies that TGFß2 is highly enriched in the pathways essential for tumor metastasis and upregulates in the metastatic ESCC tumors. High TGFß2 expression in ESCC correlates with metastasis and patient survival, and functionally contributes to tumor metastasis via activating extracellular signal-regulated kinases (ERK) signaling. By screening of a library consisting of 429 bioactive compounds, imperatorin is verified as a novel TGFß2 inhibitor, with robustly suppressive effect on tumor metastasis in multiple mice models. Mechanistically, direct binding of imperatorin and CREB1 inhibits phosphorylation, nuclear translocation of CREB1, and its interaction with TGFß2 promoter, represses TGFß2 expression and fibroblasts-secreted CCL2, and then inactivates ERK signaling to block cancer invasion and abrogates the paracrine effects of fibroblasts on tumor angiogenesis and metastasis. Overall, the findings suggest the use of TGFß2 as a diagnostic and prognostic biomarker and therapeutic target in ESCC, and supports the potential of imperatorin as a novel therapeutic strategy for cancer metastasis.

7.
Am J Cancer Res ; 9(11): 2397-2412, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815042

RESUMO

Lung cancer is the leading cause of cancer-related deaths worldwide, but effective therapeutics is limited. This study aims to identify novel anticancer strategy from a Food and Drug Administration (FDA)-approved drug library consisting of 528 compounds. Benzethonium Chloride (BZN), a FDA-approved drug for anti-infective, was found to markedly induce apoptosis and inhibit proliferation and colony formation ability of lung cancer cells in dose- and time-dependent manners. BZN also enhanced the sensitivity of lung cancer cells to gefitinib, the first-line treatment strategy for selected lung cancer patients. Furthermore, BZN significantly delayed the growth of tumor xenografts in nude mice by increasing apoptosis and decreasing Ki-67 proliferation index, without obvious toxic effects to the vital organs of animals. Mechanistically, quantitative proteomics coupled with bioinformatics analyses and a series of functional assays demonstrated that BZN induced cell cycle arrest at G1 phase, and this was associated with an increase in p38-mediated phosphorylation at threonine 286 (T286) and accelerated degradation of cyclin D1. Our findings provide the first evidence that BZN could be a promising therapeutic agent in lung cancer treatment.

8.
Theranostics ; 9(6): 1599-1613, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037126

RESUMO

Rationale: Dysregulated microRNA (miRNA) expressions in cancer can contribute to chemoresistance. This study aims to identify miRNAs that are associated with fluorouracil (5-FU) chemoresistance in esophageal squamous cell carcinoma (ESCC). The potential of miR-29c as a novel diagnostic, prognostic and treatment-predictive marker in ESCC, and its mechanisms and therapeutic implication in overcoming 5-FU chemoresistance were explored. Methods: The miRNA profiles of an ESCC cell model with acquired chemoresistance to 5-FU were analyzed using a Taqman miRNA microarray to identify novel miRNAs associated with 5-FU chemoresistance. Quantitative real-time PCR was used to determine miR-29c expression in tissue and serum samples of patients. Bioinformatics, gain- and loss-of-function experiments, and luciferase reporter assay were performed to validate F-box only protein 31 (FBXO31) as a direct target of miR-29c, and to identify potential transcription factor binding events that control miR-29c expression. The potential of systemic miR-29c oligonucleotide-based therapy in overcoming 5-FU chemoresistance was evaluated in tumor xenograft model. Results: MiR-29c, under the regulatory control of STAT5A, was frequently downregulated in tumor and serum samples of patients with ESCC, and the expression level was correlated with overall survival. Functional studies showed that miR-29c could override 5-FU chemoresistance in vitro and in vivo by directly interacting with the 3'UTR of FBXO31, leading to repression of FBXO31 expression and downstream activation of p38 MAPK. Systemically administered miR-29c dramatically improved response of 5-FU chemoresistant ESCC xenografts in vivo. Conclusions: MiR-29c modulates chemoresistance by interacting with FBXO31, and is a promising non-invasive biomarker and therapeutic target in ESCC.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/patologia , Proteínas F-Box/metabolismo , Fluoruracila/farmacologia , MicroRNAs/metabolismo , Neoplasias de Células Escamosas/patologia , Proteínas Supressoras de Tumor/metabolismo , Perfilação da Expressão Gênica , Humanos , Modelos Teóricos , Células Tumorais Cultivadas
9.
Am J Cancer Res ; 9(1): 186-197, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30755822

RESUMO

Integrin-linked kinase (ILK), which is an ankyrin repeat-containing serine/threonine protein kinase, interacts with integrin ß1 and the ß3 cytoplasmic domain and phosphorylates integrin ß1. ILK has multiple functions in cells, such as cell-extracellular matrix interactions, cell cycle, apoptosis, cell proliferation and cell motility, which are associated with the interacting partners of ILK and downstream signaling pathways. Upregulation of ILK is frequently observed in cancer tissues compared to corresponding normal tissues. Emerging evidence has demonstrated that ILK plays an important role in biological processes associated with tumorigenesis, including cancer cell proliferation, angiogenesis, metastasis, and drug resistance. Furthermore, inhibition of ILK expression and activity using siRNA or chemical inhibitors has shown a significant suppressive effect on cancer development and progression, implicating the potential of ILK as a target for cancer treatment. In this review, we summarized the functional role of ILK in tumorigenesis, with the expectation that targeting ILK could provide more evidence for cancer therapy.

10.
Food Funct ; 9(11): 5536-5546, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30207364

RESUMO

SCOPE: Colorectal cancer (CRC) is one of the most common cancers worldwide with poor survival and limited therapeutic options, and there is an urgent need to develop novel therapeutic agents with good treatment efficiency and low toxicity. This study aims to examine the anticancer bioactivity of liensinine, a constituent of Nelumbo nucifera Gaertn, in CRC and investigate the action mechanisms involved. METHODS AND RESULTS: Liensinine was found to induce apoptosis and exert a significant inhibitory effect on the proliferation and colony-forming ability of CRC cells in a dose-dependent manner without any observed cytotoxicity on normal colorectal epithelial cells. Mechanistically, our data from quantitative proteomics, western blot analysis and flow cytometry analyses demonstrated that exposure of CRC cells to liensinine caused cell cycle arrest, mitochondrial dysfunction and apoptosis, accompanied by the activation of the JNK signaling pathway. Furthermore, animal experiments showed that liensinine markedly suppressed the growth of CRC tumor xenografts in nude mice by reducing the Ki-67 proliferation index, but did not damage the vital organs of the animals. CONCLUSION: This study demonstrated for the first time that liensinine, a food-source natural product, could be a novel therapeutic strategy for treating CRC without obvious side effects.


Assuntos
Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Isoquinolinas/farmacologia , Mitocôndrias/efeitos dos fármacos , Percloratos/farmacologia , Fenóis/farmacologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Feminino , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Agric Food Chem ; 66(35): 9248-9258, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30113849

RESUMO

A library consisting of 429 food-source compounds was used to screen the natural products with anticancer properties in esophageal squamous cell carcinoma (ESCC). We demonstrated for the first time that synephrine, an active compound isolated from leaves of citrus trees, markedly suppressed cell proliferation (inhibition rate with 20 µM synephrine at day 5:71.1 ± 5.8% and 75.7 ± 6.2% for KYSE30 and KYSE270, respectively) and colony formation (inhibition rate with 10 µM synephrine: 86.5 ± 5.9% and 82.3 ± 4.5% for KYSE30 and KYSE270, respectively), as well as migration (inhibition rate with 10 µM synephrine: 76.9 ± 4.4% and 62.2 ± 5.8% for KYSE30 and KYSE270, respectively) and invasion abilities (inhibition rate with 10 µM synephrine: 73.3 ± 7.5% and 75.3 ± 3.4% for KYSE30 and KYSE270, respectively) of ESCC cells in a dose-dependent manner, without significant toxic effect on normal esophageal epithelial cells. Mechanistically, quantitative proteomics and bioinformatics analyses were performed to explore the synephrine-regulated proteins. Western blot and qRT-PCR data indicated that synephrine may downregulate Galectin-3 to inactivate AKT and ERK pathways. In addition, we found that the sensitivity of ESCC to fluorouracil (5-FU) could be enhanced by synephrine. Furthermore, in vivo experiments showed that synephrine had significant antitumor effect on ESCC tumor xenografts in nude mice (inhibition rate with 20 mg/kg synephrine is 61.3 ± 20.5%) without observed side effects on the animals. Taken together, synephrine, a food-source natural product, may be a potential therapeutic strategy in ESCC.


Assuntos
Citrus/química , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/fisiopatologia , Sistema de Sinalização das MAP Quinases , Extratos Vegetais/administração & dosagem , Sinefrina/administração & dosagem , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Galectina 3/genética , Galectina 3/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Extratos Vegetais/química , Folhas de Planta/química , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinefrina/química
12.
J Proteome Res ; 17(1): 265-275, 2018 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-29072916

RESUMO

Metastasis is one of the major causes of treatment failure in the patients with colon cancer. The aim of our study is to find key proteins and pathways that drive invasion and metastasis in colon cancer. Eight rounds of selection of cancer cells invading through matrigel-coated chamber were performed to obtain highly invasive colon cancer sublines HCT116-I8 and RKO-I8. Stable Isotope Labeling by Amino Acids in Cell Culture technology was used to identify the differently expressed proteins, and the proteomics data were analyzed by ingenuity pathway analysis. PAK1-PBD immunoprecipitation combined with Western blot were carried out to determine Cdc42 activity, and qRT-PCR and Western blot were used to determine gene expression. The functional role of Cdc42BPA and Cdc42 pathway in colon cancer invasion was studied by loss-of-function experiments including pharmacological blockade, siRNA knockdown, chamber invasion, and WST-1 assays. Human colon cancer tissue microarray was analyzed by immunohistochemistry for overexpression of Cdc42BPA and its correlation with clinicopathological parameters and patient survival outcomes. HCT116-I8 and RKO-I8 cells showed significantly stronger invasive potential as well as decreased E-cadherin and increased vimentin expressions compared with parental cells. The differently expressed proteins in I8 cells compared with parental cells were identified. Bioinformatics analysis of proteomics data suggested that Cdc42BPA protein and Cdc42 signaling pathway are important for colon cancer invasion, which was confirmed by experimental data showing upregulation of Cdc42BPA and higher expression of active GTP-bound form of Cdc42 in HCT116-I8 and RKO-I8 cells. Functionally, pharmacological and genetic blockade of Cdc42BPA and Cdc42 signaling markedly suppressed colon cancer cell invasion and reversed epithelial mesenchymal transition process. Furthermore, compared with adjacent normal tissues, Cdc42BPA expression was significantly higher in colon cancer tissues and further upregulated in metastatic tumors in lymph nodes. More importantly, Cdc42BPA expression was correlated with metastasis and poor survival of the patients with colon cancer. This study provides the first evidence that Cdc42BPA and Cdc42 signaling are important for colon cancer invasion, and Cdc42BPA has potential implications for colon cancer prognosis and treatment.


Assuntos
Neoplasias do Colo/patologia , Miotonina Proteína Quinase/metabolismo , Transdução de Sinais , Proteína cdc42 de Ligação ao GTP/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica , Prognóstico , Proteômica
13.
Am J Cancer Res ; 7(11): 2245-2256, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29218248

RESUMO

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with poor survival and limited therapeutic options. The aim of this study is to identify novel anticancer strategies from existing Food and Drug Administration (FDA)-approved drugs that have been used to clinically treat other diseases. Here, propafenone, an antiarrhythmic medication, was found to induce apoptosis and exert a significantly inhibitory effect on the proliferation and colony-forming ability of ESCC cells in a dose-dependent manner without observed cytotoxicity on normal esophageal epithelial cells. Furthermore, propafenone markedly suppressed growth of tumor xenografts in nude mice by reducing the Ki-67 proliferation index and angiogenesis but did not damage the vital organs of the animals. Mechanistically, our data from the proteomics, Western blot and flow cytometry analyses demonstrated that propafenone caused mitochondrial dysfunction as indicated by a decreased mitochondrial membrane potential and reduced expression of Bcl-xL and Bcl-2. In summary, this study provides the first evidence that propafenone, an FDA-approved drug to treat arrhythmias, could be a novel therapeutic strategy for treating ESCC without obvious side effects.

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