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1.
Elife ; 122023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37888961

RESUMO

Background: The overactivation of NF-κB signaling is a key hallmark for the pathogenesis of extranodal natural killer/T cell lymphoma (ENKTL), a very aggressive subtype of non-Hodgkin's lymphoma yet with rather limited control strategies. Previously, we found that the dysregulated exportin-1 (also known as CRM1) is mainly responsible for tumor cells to evade apoptosis and promote tumor-associated pathways such as NF-κB signaling. Methods: Herein we reported the discovery and biological evaluation of a potent small molecule CRM1 inhibitor, LFS-1107. We validated that CRM1 is a major cellular target of LFS-1107 by biolayer interferometry assay (BLI) and the knockdown of CRM1 conferred tumor cells with resistance to LFS-1107. Results: We found that LFS-1107 can strongly suppresses the growth of ENKTL cells at low-range nanomolar concentration yet with minimal effects on human platelets and healthy peripheral blood mononuclear cells. Treatment of ENKTL cells with LFS-1107 resulted in the nuclear retention of IkBα and consequent strong suppression of NF-κB transcriptional activities, NF-κB target genes downregulation and attenuated tumor cell growth and proliferation. Furthermore, LFS-1107 exhibited potent activities when administered to immunodeficient mice engrafted with human ENKTL cells. Conclusions: Therefore, LFS-1107 holds great promise for the treatment of ENKTL and may warrant translation for use in clinical trials. Funding: Yang's laboratory was supported by the National Natural Science Foundation of China (Grant: 81874301), the Fundamental Research Funds for Central University (Grant: DUT22YG122) and the Key Research project of 'be Recruited and be in Command' in Liaoning Province (Personal Target Discovery for Metabolic Diseases).


Assuntos
Linfoma Extranodal de Células T-NK , Neoplasias , Humanos , Animais , Camundongos , NF-kappa B/metabolismo , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/genética , Linfoma Extranodal de Células T-NK/patologia , Leucócitos Mononucleares/metabolismo , Transdução de Sinais , Neoplasias/metabolismo
2.
Drug Resist Updat ; 66: 100903, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36463808

RESUMO

Breast cancer stem-like cells (BCSCs) have been suggested as the underlying cause of tumor recurrence, metastasis and drug resistance in triple-negative breast cancer (TNBC). Here, we report the discovery and biological evaluation of a highly potent small-molecule antagonist of exportin-1, LFS-1107. We ascertained that exportin-1 (also named as CRM1) is a main cellular target of LFS-1107 by nuclear export functional assay, bio-layer interferometry binding assay and C528S mutant cell line. We found that LFS-1107 significantly inhibited TNBC tumor cells at low-range nanomolar concentration and LFS-1107 can selectively eliminate CD44+CD24- enriched BCSCs. We demonstrated that LFS-1107 can induce the nuclear retention of Survivin and consequent strong suppression of STAT3 transactivation abilities and the expression of downstream stemness regulators. Administration of LFS-1107 can strongly inhibit tumor growth in mouse xenograft model and eradicate BCSCs in residual tumor tissues. Moreover, LFS-1107 can significantly ablate the patient-derived tumor organoids (PDTOs) of TNBC as compared to a few approved cancer drugs. Lastly, we revealed that LFS-1107 can enhance the killing effects of chemotherapy drugs and downregulate multidrug resistance related protein targets. These new findings provide preclinical evidence of defining LFS-1107 as a promising therapeutic agent to deplete BCSCs for the treatment of TNBC.


Assuntos
Antineoplásicos , Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Feminino , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/metabolismo , Carioferinas/genética , Carioferinas/metabolismo , Carioferinas/farmacologia , Células-Tronco Neoplásicas , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/uso terapêutico , Antígeno CD24/genética , Antígeno CD24/metabolismo , Antígeno CD24/uso terapêutico
3.
Traffic ; 22(7): 221-229, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34021516

RESUMO

Dysregulation of the nuclear export machinery mediated by chromosomal maintenance 1 (CRM1, also known as exportin-1), is closely associated with various human disorders, such as breast cancer. Previously, we identified sulforaphene and its synthetic analogues as covalent inhibitors of CRM1. Herein, we describe the discovery and biological evaluation of another sulforaphene synthetic analogue, LFS-31, as a potential CRM1 inhibitor. In addition, we investigated the reversible binding mechanism of LFS-31 with CRM1 through molecular simulations coupled with bio-layer interferometry (BLI) and found relatively high binding affinity (KD = 43.1 ± 35.3 nM) between the LFS-31 and CRM1 groups. We found that LFS-31 exhibited a stronger growth suppression of triple-negative breast cancer (TNBC) cells than non-TNBC cells, and had minimal effect on normal breast cells. Pharmacological treatment of TNBC cells with LFS-31 at nanomolar concentrations led to the nuclear retention of IkBα resulting in strong suppression of NF-κB transcriptional activity and attenuated cell growth and proliferation, which collectively contributed to the antitumor responses. To the best of our knowledge, this is the first study to demonstrate the use of a sulforaphene analogue as a potent CRM1 inhibitor that targets the NF-κB signaling pathway for the targeted therapy of TNBC.


Assuntos
Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas , Transporte Ativo do Núcleo Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , NF-kappa B/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteína Exportina 1
4.
J Med Chem ; 63(8): 3881-3895, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223194

RESUMO

Exportin-1 (also named as CRM1) plays a prominent role in autoimmune disorders and has emerged as a potential therapeutic target for colitis. Here we report on the rational structure-based discovery of a small-molecule antagonist of exportin-1, LFS-829, with low-range nanomolar activities. The co-crystallographic structure, surface plasmon resonance binding assay, and cell-based phenotypic nuclear export functional assay validated that exportin-1 is a key target of LFS-829. Moreover, we demonstrated that the C528S mutation or the knockdown on exportin-1 can abolish the cellular activities of LFS-829. Strikingly, oral administration of LFS-829 can significantly reverse the pathological features of colitis model mice. We revealed that LFS-829 can attenuate dual NF-κB signaling and the Nrf2 cytoprotection pathway via targeting exportin-1 in colitis mice. Moreover, LFS-829 has a very low risk of cardiotoxicity and acute toxicity. Therefore, LFS-829 holds great promise for the treatment of colitis and may warrant translation for use in clinical trials.


Assuntos
Colite/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Sequência de Aminoácidos , Animais , Colite/metabolismo , Colite/patologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Hidrazinas/química , Carioferinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares/metabolismo , Triazóis/química , Proteína Exportina 1
5.
Angew Chem Int Ed Engl ; 59(45): 20147-20153, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33448534

RESUMO

Gallium(III)-based drugs have gained momentum in cancer therapy due to their iron-dependent anticancer activity. Judicious choice of ligands is critical for improved oral bioavailability, antitumor efficacy, and distinct mechanisms from simple GaIII salts. We describe GaIII complexes with planar tetradentate salen ligands [salen=2,3-bis[(4-dialkylamino-2-hydroxybenzylidene)amino]but-2-enedinitrile)] and labile axial solvent ligands, which display tumor growth inhibition in vitro and in vivo comparable to cisplatin. Confocal fluorescence microscopy, western blotting, mRNA profiling, chemical proteomics, and surface plasmon resonance (SPR) studies provide compelling evidence that PDIA3, a member of the protein disulfide isomerase (PDI) family involved in endoplasmic reticulum (ER) stress, is a direct target of Ga-1. This work offers a new route to designing and synthesizing Ga-based drugs, and also reveals that PDIA3 is an important anticancer target.


Assuntos
Antineoplásicos/uso terapêutico , Complexos de Coordenação/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Gálio/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Cell Physiol ; 235(4): 3626-3633, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31584203

RESUMO

Epithelial cell adhesion molecule (EpCAM), which is a transmembrane glycoprotein, is related to tumor progression. We demonstrated that EpCAM plays important roles in proliferation, apoptosis, and metastasis during breast cancer (BC) progression. But the role of N-glycosylation in EpCAM in tumor aggressiveness is not clear. Here, we evaluated the role of N-glycosylation of EpCAM in stemness and epithelial-mesenchymal transition (EMT) characteristics. EpCAM overexpression increases the expression of stemness markers (NANOG,SOX2, and OCT4) and EMT markers (N-cadherin and vimentin) under the condition of hypoxia in BC. Knockdown of EpCAM and mutation of N-glycosylation of EpCAM maintained in severe hypoxia lead to a significant reduction of stemness/EMT markers. In addition, we found that N-glycosylation of EpCAM is a crucial factor during this process. This demonstrates that EpCAM has a novel regulatory role in stemness/EMT dependence of hypoxia-inducible factor 1-alpha via regulating nuclear factor kappa B in BC cells. Hence, our study reveals EpCAM glycosylation modification as a new regulator of stemness/EMT under hypoxic in BC and points out EpCAM as a potential therapeutic target.


Assuntos
Neoplasias da Mama/genética , Molécula de Adesão da Célula Epitelial/genética , Transição Epitelial-Mesenquimal/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Apoptose/genética , Neoplasias da Mama/patologia , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Glicosilação , Humanos , Células MCF-7 , NF-kappa B/genética , Proteína Homeobox Nanog/genética , Metástase Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fator 3 de Transcrição de Octâmero/genética , Fatores de Transcrição SOXB1/genética , Transdução de Sinais/genética , Hipóxia Tumoral/genética
7.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-793336

RESUMO

@# Objective:To investigate the role and mechanism of chromosomal region maintenance 1 (CRM1) inhibitor sulforaphene (LFS-01) in killing triple negative breast cancer (TNBC) cells by inhibiting signal transducer and activator of transcription 3 (STAT3) signaling pathways. Methods: Whether LFS-01 could combine with the NES pocket of CRM1 was verified by molecular dynamics simulation techniques. The killing activity of LFS-01 on four different breast cancer cell lines was detected by CCK-8 method. TNBC MDA-MB-468 and MDA-MB-231 cells were treated with different concentrations of LFS-01, and the intracellular localization of CRM1 cargo protein STAT3 and protein with NES sequence was detected by immunofluorescence; WB was used to detect the effect of LFS-01 on the expression of STAT-3 signaling pathway and its downstream proteins; WB, cellular immunofluorescence and transmission electron microscopy were adopted to detect the occurrence of autophagy; the effect of LFS-01 on cell cycle and apoptosis was detected by flow cytometry. Results: Molecular dynamics simulations showed that LFS-01 can bind to the NES pocket of CRM1, indicating that it may structurally affect the latter's protein transport function. LFS-01 could specifically kill TNBC MDA-MB-468 and MDA-MB-231 cells. STAT3 and NES-tagged proteins were mainly blocked in the nucleus of TNBC cells after the treatment with 10 μmol/L LFS-01, while they were evenly distributed in the cytoplasm in the control group. The expressions of phosphorylated STAT3 protein, Bcl-xL and Cylin D1 were decreased in MDA-MB-468 and MDA-MB-231 cells with the increase of LFS-01 dose and the prolongation of treatment time; the expression of autophagy marker protein LC3B increased, and highdensity, multi-layered autophagosomes appeared at the same time; cell cycle arrest was observed in S phase and apoptosis rate was significantly increased (P<0.05 or P<0.01). Conclusion: LFS-01 blocks the export of CRM1 carrier protein, thereby inhibiting the activation of STAT3 signaling pathway and promoting autophagy, cell cycle arrest and apoptosis in TNBC MDA-MB-468 and MDAMB-231 cells.

8.
Tumour Biol ; 39(3): 1010428317695973, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28349835

RESUMO

Glycosylation of cell surface proteins plays an important role in the regulation of apoptosis. It has been demonstrated that knockdown of epithelial cell adhesion molecule promoted apoptosis, inhibited cell proliferation, and caused cell-cycle arrest. In this study, we investigated whether and how N-glycosylation of epithelial cell adhesion molecule influenced the apoptosis in breast cancer cells. We applied the N-glycosylation mutation epithelial cell adhesion molecule plasmid to express deglycosylation of epithelial cell adhesion molecule and then to study its function. Our results showed that deglycosylation of epithelial cell adhesion molecule promoted apoptosis and inhibited cell proliferation. Deglycosylation of epithelial cell adhesion molecule enhanced the cytotoxic effect of 5-fluorouracil, promoting apoptosis by downregulating the expression of the anti-apoptotic protein Bcl-2 and upregulating the expression of the pro-apoptotic proteins Bax and Caspase 3 via the extracellular-signal-regulated kinase 1/2 and c-Jun N-terminal kinase mitogen-activated protein kinase signaling pathways in MCF-7 and MDA-MB-231 cells. These findings are important for a better understanding of epithelial cell adhesion molecule apoptosis regulation and suggest epithelial cell adhesion molecule as a potential target for the treatment of breast cancer.


Assuntos
Neoplasias da Mama/genética , Caspase 3/biossíntese , Proliferação de Células/genética , Molécula de Adesão da Célula Epitelial/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Caspase 3/genética , Pontos de Checagem do Ciclo Celular/genética , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica , Glicosilação/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , Terapia de Alvo Molecular , Mutação
9.
Biol Chem ; 398(10): 1119-1126, 2017 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-28315854

RESUMO

Epithelial cell adhesion molecule (EpCAM) expression is elevated in breast cancer tissue, and correlates with the cancer metastasis and cell adhesion. Although EpCAM glycosylation is supposed to be associated with its function, the contribution of N-glycosylation to its function remains unclear. Here we analyzed cell adhesion ability of EpCAM in breast cancer cells. The results showed that EpCAM expression was associated with cell adhesion and N-glycosylation mutation of EpCAM decreased adhesion capacity. N-glycosylation mutation of EpCAM was correlated with lower levels of integrin ß1 and fibronectin. We also found that effect of N-glycosylation of EpCAM on cell adhesion was regulated via FAK/Akt/Gsk-3ß/ß-catenin signaling pathway, which further adjusted MMP2/9 expression and activities. Our studies identified the characteristics and function of EpCAM glycosylation sites on breast cancer cell adhesion. These data could potentially clarify molecular regulation of EpCAM by N-glycosylation and intensify our understanding of the utility of glycosylated EpCAM as a target for breast cancer therapy.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Adesão Celular/genética , Molécula de Adesão da Célula Epitelial/genética , Molécula de Adesão da Célula Epitelial/metabolismo , Mutação , Neoplasias da Mama/metabolismo , Molécula de Adesão da Célula Epitelial/química , Feminino , Glicosilação , Humanos , Células Tumorais Cultivadas
10.
Oncotarget ; 6(29): 27187-98, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26356670

RESUMO

Epithelial cell adhesion molecule (EpCAM) is a type I transmembrane protein that is expressed in the majority of normal epithelial tissues and is overexpressed in most epithelial cancers including breast cancer, where it plays an important role in cancer progression. However, the mechanism by which EpCAM promotes the progression of breast cancer is not understood. In this study, we found that EpCAM expression was increased in tumor tissue from breast cancer patients compared to healthy patients. Overexpression of EpCAM in breast cancer cells enhanced tumor cell growth in vitro and increased invasiveness, whereas small interfering RNA-mediated silencing of EpCAM (si-EpCAM) had the opposite effect. EpCAM knockdown led to decreased phosphorylation of Raf and ERK, suppression of malignant behavior of breast cancer cells, and inhibition of the Ras/Raf/ERK signaling pathway. Furthermore, si-EpCAM-mediated invasion and metastasis of breast carcinoma cells required the downregulation of matrix metalloproteinase-9 (MMP-9) through inhibition of this signaling pathway. In conclusion, our data show that knockdown of EpCAM can inhibition breast cancer cell growth and metastasis via inhibition of the Ras/Raf/ERK signaling pathway and MMP-9.


Assuntos
Antígenos de Neoplasias/metabolismo , Neoplasias da Mama/metabolismo , Moléculas de Adesão Celular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/química , Quinases raf/metabolismo , Proteínas ras/metabolismo , Adulto , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Molécula de Adesão da Célula Epitelial , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Imuno-Histoquímica , Células MCF-7 , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Fosforilação , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Quinases raf/antagonistas & inibidores , Proteínas ras/antagonistas & inibidores
11.
J Cell Physiol ; 230(4): 775-82, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25205054

RESUMO

The epithelial-to-mesenchymal transition (EMT), a process involving the breakdown of cell-cell junctions and loss of epithelial polarity, is closely related to cancer metastasis and invasion. The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane protein expressed in the majority of normal epithelial tissues and overexpressed in the majority of human epithelial cancers including breast cancer. EpCAM plays an important role in cancer progression. We showed that EpCAM participated in TGF-ß1-induced EMT. TGF-ß1 treatment of MCF-7 breast cancer cells was shown to induce EpCAM expression, which promoted the EMT and cell migration. EpCAM overexpression further enhanced TGF-ß1-induced EMT and EpCAM knockdown inhibited TGF-ß1-induced EMT. We further demonstrated that TGF-ß1 treatment induced the phosphorylation of JNK that was in turn responsible for the increased expression of Jun and Fos. This result suggests an important role of the JNK to AP-1 signaling to EpCAM downstream of TGF-ß1 for the induction of EMT in the breast cancer cells. Collectively, our study highlights a novel function for EpCAM in TGF-ß1-induced EMT process and suggests that targeting of EpCAM may be an attractive strategy to treat breast cancer. This study implicates the potential value of EpCAM as a molecular marker for breast cancer.


Assuntos
Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Transdução de Sinais/fisiologia , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Células Cultivadas , Molécula de Adesão da Célula Epitelial , Transição Epitelial-Mesenquimal/genética , Humanos , Células MCF-7 , Fator de Transcrição AP-1/genética
12.
PLoS One ; 9(7): e102590, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25019346

RESUMO

Resistance to fluoropyrimidine-based chemotherapy is the main reason for the failure of cancer treatment, and drug resistance is associated with an inability of tumor cells to undergo apoptosis in response to treatment. Alterations in the expression of epithelial cell adhesion molecule (EpCAM) affect the sensitivity or resistance of tumor cells to anticancer treatment and the activity of intracellular signaling pathways. However, the role of EpCAM in the induction of apoptosis in breast cancer cells remains unclear. Here, we investigated the effect of EpCAM gene knockdown on chemosensitivity to 5-fluorouracil (5-FU) in MCF-7 cells and explored the underlying mechanisms. Our results showed that knockdown of EpCAM promoted apoptosis, inhibited cell proliferation and caused cell-cycle arrest. EpCAM knockdown enhanced the cytotoxic effect of 5-FU, promoting apoptosis by downregulating the expression of the anti-apoptotic protein Bcl-2 and upregulating the expression of the pro-apoptotic proteins Bax, and caspase3 via the ERK1/2 and JNK MAPK signaling pathways in MCF-7 cells. These results indicate that knockdown of EpCAM may have a tumor suppressor effect and suggest EpCAM as a potential target for the treatment of breast cancer.


Assuntos
Antígenos de Neoplasias/fisiologia , Antineoplásicos/farmacologia , Moléculas de Adesão Celular/fisiologia , Fluoruracila/farmacologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Caspase 3/genética , Caspase 3/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Molécula de Adesão da Célula Epitelial , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Células MCF-7 , Transdução de Sinais , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
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