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1.
J Hematol Oncol ; 17(1): 5, 2024 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-38233872

RESUMO

Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies.


Assuntos
Fatores de Troca do Nucleotídeo Guanina , Neoplasias , Humanos , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Microambiente Tumoral , Transdução de Sinais , AMP Cíclico/metabolismo , AMP Cíclico/farmacologia
2.
J Hematol Oncol ; 16(1): 8, 2023 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-36755342

RESUMO

RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize "immune-cold" tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy.


Assuntos
Imunidade Inata , Neoplasias , Humanos , Transdução de Sinais , Neoplasias/terapia , RNA , Imunoterapia
3.
Int J Biol Sci ; 18(8): 3167-3177, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35637967

RESUMO

Gamma synuclein (SNCG) is a neuronal protein that is also aberrantly overexpressed in various types of human cancer. SNCG overexpression promotes cancer invasion and metastasis. However, the mechanisms that drive cancer metastasis upon SNCG expression remain elusive. Elucidation of the mechanisms underlying the promotion of cancer metastasis by SNCG may help discover therapeutic avenues for SNCG-overexpressed cancer. Here, we show that SNCG promotes transforming growth factor-ß (TGF-ß)-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation. Mechanistically, SNCG promotes p38MAPK phosphorylation by interacting with the MAPK kinase 3/6 (MKK3/6) and prevents their degradation. SNCG knockdown leads to a decrease in TGF-ß-induced phosphorylation of MKK3/6; and abrogates the induction of matrix metalloproteinase (MMP)-9 expression by TGF-ß and its target gene Twist1. Furthermore, p38MAPK inhibition abrogates the promotion of MMP-9 expression and cancer cell invasion by SNCG. Both p38MAPK and MMP inhibitors can suppress the promotion of cancer cell invasion by SNCG. Finally, overexpression of SNCG in liver cancer cells promotes lung metastasis, which can be suppressed by the p38MAPK inhibitor. Together, our data uncover a previously unknown role of SNCG in promoting TGF-ß-MKK3/6-p38MAPK signaling. This study highlights the critical role of p38MAPK in the promotion of cancer metastasis by SNCG, and indicates that p38MAPK inhibitor may serve as a potential therapeutic for SNCG-overexpressed cancer.


Assuntos
Sistema de Sinalização das MAP Quinases , Metástase Neoplásica , gama-Sinucleína , Humanos , MAP Quinase Quinase 3 , MAP Quinase Quinase 6 , Sistema de Sinalização das MAP Quinases/genética , Invasividade Neoplásica , Proteínas de Neoplasias , Fator de Crescimento Transformador beta/metabolismo , gama-Sinucleína/genética , gama-Sinucleína/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Int J Cancer ; 151(6): 833-842, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35322886

RESUMO

Collagens are the main components of extracellular matrix in the tumor microenvironment. Both fibrillar and nonfibrillar collagens are involved in tumor progression. The nonfibrillar network-forming collagens such as type IV and type VIII collagens are frequently overexpressed in various types of human cancers, which promotes tumor cell proliferation, adhesion, invasion, metastasis and angiogenesis. Studies on the roles of these collagens have shed light on the mechanisms underpinning the effects of this protein family. Future research has to explicit the role of network-forming collagens with respect to cancer progression and treatment. Herein, we review the regulation of network-forming collagens expression in cancer; the roles of network-forming collagens in tumor invasion, metastasis and angiogenesis; and the clinical significance of network-forming collagens expression in cancer patients.


Assuntos
Colágeno , Neoplasias , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Humanos , Colágenos não Fibrilares , Microambiente Tumoral
5.
J Hematol Oncol ; 15(1): 34, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35331296

RESUMO

Cancer microenvironment is critical for tumorigenesis and cancer progression. The extracellular matrix (ECM) interacts with tumor and stromal cells to promote cancer cells proliferation, migration, invasion, angiogenesis and immune evasion. Both ECM itself and ECM stiffening-induced mechanical stimuli may activate cell membrane receptors and mechanosensors such as integrin, Piezo1 and TRPV4, thereby modulating the malignant phenotype of tumor and stromal cells. A better understanding of how ECM stiffness regulates tumor progression will contribute to the development of new therapeutics. The rapidly expanding evidence in this research area suggests that the regulators and effectors of ECM stiffness represent potential therapeutic targets for cancer. This review summarizes recent work on the regulation of ECM stiffness in cancer, the effects of ECM stiffness on tumor progression, cancer immunity and drug resistance. We also discuss the potential targets that may be druggable to intervene ECM stiffness and tumor progression. Based on these advances, future efforts can be made to develop more effective and safe drugs to interrupt ECM stiffness-induced oncogenic signaling, cancer progression and drug resistance.


Assuntos
Matriz Extracelular , Neoplasias , Carcinogênese/metabolismo , Matriz Extracelular/metabolismo , Humanos , Integrinas/metabolismo , Canais Iônicos/metabolismo , Neoplasias/patologia , Oncogenes , Microambiente Tumoral
6.
J Hematol Oncol ; 14(1): 128, 2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34419139

RESUMO

Biomarkers-guided precision therapeutics has revolutionized the clinical development and administration of molecular-targeted anticancer agents. Tailored precision cancer therapy exhibits better response rate compared to unselective treatment. Protein kinases have critical roles in cell signaling, metabolism, proliferation, survival and migration. Aberrant activation of protein kinases is critical for tumor growth and progression. Hence, protein kinases are key targets for molecular targeted cancer therapy. The serine/threonine kinase Akt is frequently activated in various types of cancer. Activation of Akt promotes tumor progression and drug resistance. Since the first Akt inhibitor was reported in 2000, many Akt inhibitors have been developed and evaluated in either early or late stage of clinical trials, which take advantage of liquid biopsy and genomic or molecular profiling to realize personalized cancer therapy. Two inhibitors, capivasertib and ipatasertib, are being tested in phase III clinical trials for cancer therapy. Here, we highlight recent progress of Akt signaling pathway, review the up-to-date data from clinical studies of Akt inhibitors and discuss the potential biomarkers that may help personalized treatment of cancer with Akt inhibitors. In addition, we also discuss how Akt may confer the vulnerability of cancer cells to some kinds of anticancer agents.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Br J Pharmacol ; 178(21): 4389-4407, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34233013

RESUMO

BACKGROUND AND PURPOSE: The multikinase inhibitor sorafenib is a first-line drug for advanced hepatocellular carcinoma. The response to sorafenib varies among hepatocellular carcinoma patients and many of the responders suffer from reduced sensitivity after long-term treatment. This study aims to explore a novel strategy to potentiate or maximize the anti-hepatocellular carcinoma effects of sorafenib. EXPERIMENTAL APPROACH: We used hepatocellular carcinoma cell lines, western blotting, various antagonists, siRNA and tumour xenografts mouse model to determine the anti- hepatocellular carcinoma effects of sorafenib in combination with berbamine or other Na+ /K+ -ATPase ligands. KEY RESULTS: Berbamine and the cardiotonic steroid, ouabain, synergize with sorafenib to inhibit hepatocellular carcinoma cells growth. Mechanistically, berbamine induces Src phosphorylation in Na+ /K+ -ATPase-dependent manner, leading to the activation of p38MAPK and EGFR-ERK pathways. The Na+ /K+ -ATPase ligand ouabain also induces Src, EGFR, type I insulin-like growth factor receptor, ERK1/2 and p38MAPK phosphorylation in hepatocellular carcinoma cells. Treatment of hepatocellular carcinoma cells with Src or EGFR inhibitor inhibits the induction of ERK1/2 phosphorylation by berbamine. Moreover, sorafenib inhibits the induction of Src, p38MAPK, EGFR and ERK1/2 phosphorylation by berbamine and ouabain. Importantly, combination of sorafenib with berbamine or ouabain synergistically inhibits both sorafenib-naïve and sorafenib-resistant hepatocellular carcinoma cells growth. Co-treatment of hepatocellular carcinoma cells with berbamine and sorafenib significantly induces cell death and significantly inhibits hepatocellular carcinoma xenografts growth in vivo. CONCLUSION AND IMPLICATIONS: Berbamine or other Na+ /K+ -ATPase ligands have a potential for improving sorafenib responsiveness in hepatocellular carcinoma. Targeting Na+ /K+ -ATPase represents a novel strategy to potentiate the anti- hepatocellular carcinoma effects of sorafenib.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Benzilisoquinolinas , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Ouabaína/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Sorafenibe/farmacologia , Quinases da Família src/metabolismo
8.
Cancers (Basel) ; 13(7)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917483

RESUMO

Aspirin can prevent or inhibit inflammation-related cancers, such as colorectal cancer and hepatocellular carcinoma (HCC). However, the effectiveness of chemotherapy may be compromised by activating oncogenic pathways in cancer cells. Elucidation of such chemoresistance mechanisms is crucial to developing novel strategies to maximize the anti-cancer effects of aspirin. Here, we report that aspirin markedly induces CREB/ATF1 phosphorylation in HCC cells, which compromises aspirin's anti-HCC effect. Inhibition of AMP-activated protein kinase (AMPK) abrogates the induction of CREB/ATF1 phosphorylation by aspirin. Mechanistically, activation of AMPK by aspirin results in decreased expression of the urea cycle enzyme carbamoyl-phosphate synthase 1 (CPS1) in HCC cells and xenografts. Treatment with aspirin or CPS1 knockdown stimulates soluble adenylyl cyclase expression, thereby increasing cyclic AMP (cAMP) synthesis and stimulating PKA-CREB/ATF1 signaling. Importantly, abrogation of aspirin-induced CREB/ATF1 phosphorylation could sensitize HCC to aspirin. The bis-benzylisoquinoline alkaloid berbamine suppresses the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), leading to protein phosphatase 2A-mediated downregulation of CREB/ATF1 phosphorylation. The combination of berbamine and aspirin significantly inhibits HCC in vitro and in vivo. These data demonstrate that the regulation of cAMP-PKA-CREB/ATF1 signaling represents a noncanonical function of CPS1. Targeting the PKA-CREB/ATF1 axis may be a strategy to improve the therapeutic effects of aspirin on HCC.

9.
Exp Hematol Oncol ; 10(1): 17, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622411

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the common cancers that are very aggressive. The secreted cytokine transforming growth factor-ß (TGF-ß) promotes cancer metastasis by multiple mechanisms such as epithelial-mesenchymal transition and immune evasion. The canonical TGF-ß signaling is largely mediated by smooth muscle actin/mothers against decapentaplegic (SMAD) proteins. The current study aims to explore the regulation of TGF-ß/SMAD signaling by selenophosphate synthetase 1 (SEPHS1). METHODS: Immunohistochemistry was used to detect the expression of SEPHS1 in HCC and adjacent liver tissues. Western blotting and quantitative reverse-transcription PCR were used to detect the protein and mRNA levels in HCC cell lines. Cell migration and invasion were determined by transwell assay. Bioinformatic analysis was conducted to determine SEPHS1 expression in HCC and its correlation with the survival of HCC patients. RESULTS: Here we report that SEPHS1 is a positive regulator of SMAD proteins. SEPHS1 expression is up-regulated in HCC compared with adjacent liver tissues. SEPHS1 knockdown leads to decreased expression of SMAD2/3/4 and mesenchymal markers including snail, slug and N-cadherin in HCC cells. Furthermore, SEPHS1 knockdown results in a decrease in HCC cells migration and invasion, and suppresses the stimulation of HCC cells migration and invasion by TGF-ß. Overexpression of SEPHS1 in HCC cells promotes cell invasion, which can be abrogated by SMAD3 knockdown. Lastly, higher expression of SEPHS1 is correlated with poor prognosis in HCC patients, as manifested by decreased overall survival and disease-free survival. CONCLUSIONS: SEPHS1 is a positive regulator of TGF-ß/SMAD signaling that is up-regulated in HCC. Increased SEPHS1 expression may indicate poor prognosis for patients with HCC.

10.
Mol Oncol ; 15(5): 1543-1565, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33605506

RESUMO

Early and accurate diagnosis of prostate cancer (PCa) is extremely important, as metastatic PCa remains hard to treat. EWI-2, a member of the Ig protein subfamily, is known to inhibit PCa cell migration. In this study, we found that EWI-2 localized on both the cell membrane and exosomes regulates the distribution of miR-3934-5p between cells and exosomes. Interestingly, we observed that EWI-2 is localized not only on the plasma membrane but also on the nuclear envelope (nuclear membrane), where it regulates the nuclear translocation of signaling molecules and miRNA. Collectively, these functions of EWI-2 found in lipid bilayers appear to regulate PCa cell metastasis through the epidermal growth factor receptor-mitogen-activated protein kinase-extracellular-signal-regulated kinase (EGFR-MAPK-ERK) pathway. Our research provides new insights into the molecular function of EWI-2 on PCa metastasis, and highlights EWI-2 as a potential PCa biomarker.


Assuntos
Adenocarcinoma/patologia , Antígenos CD/fisiologia , Proteínas de Membrana/fisiologia , MicroRNAs/metabolismo , Neoplasias da Próstata/patologia , Transporte Ativo do Núcleo Celular/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Antígenos CD/genética , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Receptores ErbB/metabolismo , Exossomos/metabolismo , Exossomos/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transporte de RNA/genética , Transdução de Sinais/genética
11.
Exp Hematol Oncol ; 9(1): 32, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33292604

RESUMO

Cyclic adenosine monophosphate (cAMP) is the first discovered second messenger, which plays pivotal roles in cell signaling, and regulates many physiological and pathological processes. cAMP can regulate the transcription of various target genes, mainly through protein kinase A (PKA) and its downstream effectors such as cAMP-responsive element binding protein (CREB). In addition, PKA can phosphorylate many kinases such as Raf, GSK3 and FAK. Aberrant cAMP-PKA signaling is involved in various types of human tumors. Especially, cAMP signaling may have both tumor-suppressive and tumor-promoting roles depending on the tumor types and context. cAMP-PKA signaling can regulate cancer cell growth, migration, invasion and metabolism. This review highlights the important roles of cAMP-PKA-CREB signaling in tumorigenesis. The potential strategies to target this pathway for cancer therapy are also discussed.

12.
J Hematol Oncol ; 13(1): 64, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493414

RESUMO

Insulin-like growth factors (IGFs) play important roles in mammalian growth, development, aging, and diseases. Aberrant IGFs signaling may lead to malignant transformation and tumor progression, thus providing the rationale for targeting IGF axis in cancer. However, clinical trials of the type I IGF receptor (IGF-IR)-targeted agents have been largely disappointing. Accumulating evidence demonstrates that the IGF axis not only promotes tumorigenesis, but also confers resistance to standard treatments. Furthermore, there are diverse pathways leading to the resistance to IGF-IR-targeted therapy. Recent studies characterizing the complex IGFs signaling in cancer have raised hope to refine the strategies for targeting the IGF axis. This review highlights the biological activities of IGF-IR signaling in cancer and the contribution of IGF-IR to cytotoxic, endocrine, and molecular targeted therapies resistance. Moreover, we update the diverse mechanisms underlying resistance to IGF-IR-targeted agents and discuss the strategies for future development of the IGF axis-targeted agents.


Assuntos
Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica , Resistencia a Medicamentos Antineoplásicos/fisiologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/fisiologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor IGF Tipo 1/fisiologia , Transdução de Sinais/fisiologia , Somatomedinas/fisiologia , Antineoplásicos/farmacologia , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Núcleo Celular/metabolismo , Fenômenos Fisiológicos Celulares/efeitos dos fármacos , Fenômenos Fisiológicos Celulares/fisiologia , Autorrenovação Celular/fisiologia , Ensaios Clínicos como Assunto , Terapia Combinada , Dano ao DNA , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/efeitos da radiação , Progressão da Doença , Desenvolvimento de Medicamentos , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Integrinas/fisiologia , Metástase Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/fisiopatologia , Neoplasias/radioterapia , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Microambiente Tumoral
13.
J Hematol Oncol ; 12(1): 71, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277692

RESUMO

Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase ß-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
14.
J Biol Chem ; 294(15): 5945-5955, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30782845

RESUMO

GADD34 (growth arrest and DNA damage-inducible gene 34) plays a critical role in responses to DNA damage and endoplasmic reticulum stress. GADD34 has opposing effects on different stimuli-induced cell apoptosis events, but the reason for this is unclear. Here, using immunoblotting analyses and various molecular genetic approaches in HepG2 and SMMC-7721 cells, we demonstrate that GADD34 protects hepatocellular carcinoma (HCC) cells from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by stabilizing a BCL-2 family member, myeloid cell leukemia 1 (MCL-1). We found that GADD34 knockdown decreased MCL-1 levels and that GADD34 overexpression up-regulated MCL-1 expression in HCC cells. GADD34 did not affect MCL-1 transcription but enhanced MCL-1 protein stability. The proteasome inhibitor MG132 abrogated GADD34 depletion-induced MCL-1 down-regulation, suggesting that GADD34 inhibits the proteasomal degradation of MCL-1. Furthermore, GADD34 overexpression promoted extracellular signal-regulated kinase (ERK) phosphorylation through a signaling axis that consists of the E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6) and transforming growth factor-ß-activated kinase 1 (MAP3K7)-binding protein 1 (TAB1), which mediated the up-regulation of MCL-1 by GADD34. Of note, TRAIL up-regulated both GADD34 and MCL-1 levels, and knockdown of GADD34 and TRAF6 suppressed the induction of MCL-1 by TRAIL. Correspondingly, GADD34 knockdown potentiated TRAIL-induced apoptosis, and MCL-1 overexpression rescued TRAIL-treated and GADD34-depleted HCC cells from cell death. Taken together, these findings suggest that GADD34 inhibits TRAIL-induced HCC cell apoptosis through TRAF6- and ERK-mediated stabilization of MCL-1.


Assuntos
Apoptose , Carcinoma Hepatocelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína Fosfatase 1/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , MAP Quinases Reguladas por Sinal Extracelular/genética , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas de Neoplasias/genética , Proteína Fosfatase 1/genética , Estabilidade Proteica , Fator 6 Associado a Receptor de TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética
15.
Med Res Rev ; 39(1): 114-145, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29855050

RESUMO

The nonsteroidal anti-inflammatory agent aspirin is widely used for preventing and treating cardiovascular and cerebrovascular diseases. In addition, epidemiologic evidences reveal that aspirin may prevent a variety of human cancers, while data on the association between aspirin and some kinds of cancer are conflicting. Preclinical studies and clinical trials also reveal the therapeutic effect of aspirin on cancer. Although cyclooxygenase is a well-known target of aspirin, recent studies uncover other targets of aspirin and its metabolites, such as AMP-activated protein kinase, cyclin-dependent kinase, heparanase, and histone. Accumulating evidence demonstrate that aspirin may act in different cell types, such as epithelial cell, tumor cell, endothelial cell, platelet, and immune cell. Therefore, aspirin acts on diverse hallmarks of cancer, such as sustained tumor growth, metastasis, angiogenesis, inflammation, and immune evasion. In this review, we focus on recent progress in the use of aspirin for cancer chemoprevention and therapy, and integratively analyze the mechanisms underlying the anticancer effects of aspirin and its metabolites. We also discuss mechanisms of aspirin resistance and describe some derivatives of aspirin, which aim to overcome the adverse effects of aspirin.


Assuntos
Aspirina/uso terapêutico , Quimioprevenção , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Aspirina/efeitos adversos , Aspirina/química , Biomarcadores Tumorais/metabolismo , Ensaios Clínicos como Assunto , Humanos , Neoplasias/epidemiologia
16.
Exp Hematol Oncol ; 7: 24, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250760

RESUMO

Estrogen is a steroid hormone that has critical roles in reproductive development, bone homeostasis, cardiovascular remodeling and brain functions. However, estrogen also promotes mammary, ovarian and endometrial tumorigenesis. Estrogen antagonists and drugs that reduce estrogen biosynthesis have become highly successful therapeutic agents for breast cancer patients. The effects of estrogen are largely mediated by estrogen receptor (ER) α and ERß, which are members of the nuclear receptor superfamily of transcription factors. The mechanisms underlying the aberrant expression of ER in breast cancer and other types of human tumors are complex, involving considerable alternative splicing of ERα and ERß, transcription factors, epigenetic and post-transcriptional regulation of ER expression. Elucidation of mechanisms for ER expression may not only help understand cancer progression and evolution, but also shed light on overcoming endocrine therapy resistance. Herein, we review the complex mechanisms for regulating ER expression in human cancer.

17.
Oncol Lett ; 16(3): 4073-4077, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30128030

RESUMO

Poly(ADP-Ribose) polymerase family member 9 (PARP9) promotes the proliferation, survival and chemotherapy resistance in lymphoma and prostate cancer. The expression and function of PARP9 in human breast cancer remains unknown. In the present study, it was demonstrated that PARP9 is frequently overexpressed in human breast cancer. In 57 normal breast tissues, the expression of PARP9 was not detected in 43 cases (75.4%), but low levels of PARP9 were detected in 13 cases (22.8%), and modest levels of PARP9 (PARP9/GAPDH ratio ~1:1) were detected in only 1 case (1.7%). In contrast, the expression of PARP9 was detected in all 57 breast cancer tissues, in which the levels of PARP9 were higher than that in paired normal breast tissues. In addition, high levels of PARP9 were detected in 43.8% of breast cancer tissues. Overexpression of PARP9 was negatively associated with estrogen receptor expression, and positively associated with axillary lymph node metastasis. However, PARP9 expression was not associated with other clinicopathological parameters, including age, HER-2 and tumor size. Furthermore, PARP9-knockdown inhibited breast cancer cell migration. These data indicate that PARP9 may promote breast cancer progression.

18.
Cell Death Dis ; 9(6): 625, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29795373

RESUMO

Transforming growth factor ß (TGF-ß) is critical for embryonic development, adult tissue homeostasis, and tumor progression. TGF-ß suppresses tumors at early stage, but promotes metastasis at later stage through oncogenes such as Twist1. Gamma-synuclein (SNCG) is overexpressed in a variety of invasive and metastatic cancer. Here, we show that TGF-ß induces SNCG expression by Smad-Twist1 axis, thus promoting TGF-ß- and Twist1-induced cancer cell migration and invasion. We identify multiple Twist1-binding sites (E-boxes) in SNCG promoter. Chromatin immunoprecipitation and luciferase assays confirm the binding of Twist1 to the E-boxes of SNCG promoter sequence (-129/-1026 bp). Importantly, the Twist1-binding site close to the transcription initiation site is critical for the upregulation of SNCG expression by TGF-ß and Twist1. Mutations of Twist1 motif on the SNCG promoter constructs markedly reduces the promoter activity. We further show that TGF-ß induces Twist1 expression through Smad thereby enhancing the binding of Twist1 to SNCG promoter, upregulating SNCG promoter activity and increasing SNCG expression. SNCG knockdown abrogates TGF-ß- or Twist1-induced cancer cell migration and invasion. Finally, SNCG knockdown inhibits the promotion of cancer metastasis by Twist1. Together, our data demonstrate that SNCG is a novel target of TGF-ß-Smad-Twist1 axis and a mediator of Twist1-induced cancer metastasis.


Assuntos
Movimento Celular , Proteínas Nucleares/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Proteína 1 Relacionada a Twist/metabolismo , gama-Sinucleína/metabolismo , Elementos E-Box , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Células Hep G2 , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Regiões Promotoras Genéticas , Proteínas Smad/metabolismo , Regulação para Cima/efeitos dos fármacos , gama-Sinucleína/genética
19.
J Cell Mol Med ; 22(1): 589-599, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29024409

RESUMO

The natural agent rhein is an ananthraquinone derivative of rhubarb, which has anticancer effects. To determine the mechanisms underlying the anticancer effects of rhein, we detected the effect of rhein on several oncoproteins. Here, we show that rhein induces ß-catenin degradation in both hepatoma cell HepG2 and cervical cancer cell Hela. Treatment of HepG2 and Hela cells with rhein shortens the half-life of ß-catenin. The proteasome inhibitor MG132 blunts the downregulation of ß-catenin by rhein. The induction of ß-catenin degradation by rhein is dependent on GSK3 but independent of Akt. Treatment of HepG2 and Hela cells with GSK3 inhibitor or GSK3ß knockdown abrogates the effect of rhein on ß-catenin. GSK3ß knockdown compromises the inhibition of HepG2 and Hela cell growth by rhein. Furthermore, rhein dose not downregulate ß-catenin mutant that is deficient of phosphorylation at multiple residues including Ser33, Ser37, Thr41 and Ser45. Moreover, rhein induces cell cycle arrest at S phase in both HepG2 and Hela cells. Intraperitoneal administration of rhein suppresses tumour cells proliferation and tumour growth in HepG2 xenografts model. Finally, the levels of ß-catenin are reduced in rhein-treated tumours. These data demonstrate that rhein can induce ß-catenin degradation and inhibit tumour growth.


Assuntos
Antraquinonas/farmacologia , Produtos Biológicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias/patologia , Proteólise/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HeLa , Células Hep G2 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fase S/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 34(3): 415-420, 2017 Jun 01.
Artigo em Chinês | MEDLINE | ID: mdl-29745508

RESUMO

AMP-activated protein kinase (AMPK) is involved in the development and progression of tumors including hepatocellular carcinoma (HCC). However, studies on AMPK and tumorigenesis were largely based on experiments in vitro or tumor xenografts model. Here, we introduce a liver-specific AMPKα1 knockout mice model, which is achieved by Alb-Cre recombinase system. The expression of AMPKα1 in the liver of AMPKα1 -/--Alb-Cre mice is absent. AMPKα1 knockout in the liver does not affect the growth and histological structure of mouse liver. This model provides a favorable tool to the study of the roles of AMPKα1 in liver metabolism or tumorigenesis.

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