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1.
Theranostics ; 9(12): 3541-3554, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281496

RESUMO

Rationale: Advanced nasopharyngeal carcinoma (NPC) is an aggressive disease with no targeted therapies and poor outcomes. New innovative targets are urgently needed. KLF4 has been extensively studied in the context of tumors, and current data suggest that it can act as either a tissue-specific tumor-inhibiting or a tumor-promoting gene. Here, we found that KLF4 played as a tumor-promoting gene in NPC, and could be mediated by PLK1. Methods: Tissue immunohistochemistry (IHC) assay was performed to identify the role of KLF4 in NPC. Global gene expression experiments were performed to explore the molecular mechanisms underlying KLF4-dependent tumorigenesis. Small-molecule kinase inhibitor screening was performed to identify potential upstream kinases of KLF4. The pharmacologic activity of polo-like kinase inhibitor volasertib (BI6727) in vitro and in vivo was determined. Result: Our investigation showed that high expression of KLF4 was correlated with poor prognosis in NPC. Moreover, genome-wide profiling revealed that KLF4 directly activated oncogenic programmes, including gene sets associated with KRAS, VEGF, and MYC signalling. We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. Moreover, KLF4 could enhance TRAF6 expression at the transcriptional level, thus initiating a KLF4-TRAF6 feed-forward loop. Treatment with the PLK1 inhibitor volasertib (BI6727) significantly inhibited tumor growth in nude mice. Conclusion: Our study unveiled a new PLK1-TRAF6-KLF4 feed-forward loop. The resulting increase in KLF4 ubiquitination leads to stabilization and upregulation of KLF4, which leads to tumorigenesis in NPC. These results expand our understanding of the role of KLF4 in NPC and validate PLK1 inhibitors as potential therapeutic agents for NPC, especially cancer patients with KLF4 overexpression.

2.
Clin Cancer Res ; 25(14): 4530-4541, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30940655

RESUMO

PURPOSE: Immune checkpoint blockade (ICB) therapy induces durable tumor regressions in a minority of patients with cancer. In this study, we aimed to identify kinase inhibitors that were capable of increasing the antimelanoma immunity. EXPERIMENTAL DESIGN: Flow cytometry-based screening was performed to identify kinase inhibitors that can block the IFNγ-induced PD-L1 expression in melanoma cells. The pharmacologic activities of regorafenib alone or in combination with immunotherapy in vitro and in vivo were determined. The mechanisms of regorafenib were explored and analyzed in melanoma patients treated with or without anti-PD-1 using The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. RESULTS: Through screening of a kinase inhibitor library, we found approximately 20 agents that caused more than half reduction of cell surface PD-L1 level, and regorafenib was one of the most potent agents. Furthermore, our results showed that regorafenib, in vitro and in vivo, strongly promoted the antitumor efficacy when combined with IFNγ or ICB. By targeting the RET-Src axis, regorafenib potently inhibited JAK1/2-STAT1 and MAPK signaling and subsequently attenuated the IFNγ-induced PD-L1 and IDO1 expression without affecting MHC-I expression much. Moreover, RET and Src co-high expression was an independent unfavorable prognosis factor in melanoma patients with or without ICB through inhibiting the antitumor immune response. CONCLUSIONS: Our data unveiled a new mechanism of alleviating IFNγ-induced PD-L1 and IDO1 expression and provided a rationale to explore a novel combination of ICB with regorafenib clinically, especially in melanoma with RET/Src axis activation.

3.
Autophagy ; 14(4): 671-684, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28980855

RESUMO

Impaired macroautophagy/autophagy and high levels of glycolysis are prevalent in liver cancer. However, it remains unknown whether there is a regulatory relationship between autophagy and glycolytic metabolism. In this study, by utilizing cancer cells with basal or impaired autophagic flux, we demonstrated that glycolytic activity is negatively correlated with autophagy level. The autophagic degradation of HK2 (hexokinase 2), a crucial glycolytic enzyme catalyzing the conversion of glucose to glucose-6-phosphate, was found to be involved in the regulation of glycolysis by autophagy. The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation. In a tissue microarray of human liver cancer, the combination of high HK2 expression and high SQSTM1 expression was shown to have biological and prognostic significance. Furthermore, 3-BrPA, a pyruvate analog targeting HK2, significantly decreased the growth of autophagy-impaired tumors in vitro and in vivo (p < 0.05). By demonstrating the regulation of glycolysis by autophagy through the TRAF6- and SQSTM1-mediated ubiquitination system, our study may open an avenue for developing a glycolysis-targeting therapeutic intervention for treatment of autophagy-impaired liver cancer.

4.
J Cancer ; 8(17): 3464-3473, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29151930

RESUMO

Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase and works as an oncogene in various cancers. Recently, PTK6 has been used as a therapeutic target for breast cancer patients in a clinical study. However, the prognostic value of PTK6 in bladder cancer (BC) remains vague. Therefore, we retrieved 3 independent investigations of Oncomine database and found that PTK6 is highly expressed in BC tissues compared with corresponding normal controls. Similar results were also observed in clinical specimens at both mRNA and protein levels. Immunohistochemical analysis indicated that PTK6 overexpression was highly related to the T classification, N classification, grade, recurrence, and poor prognosis of BC patients. Furthermore, we demonstrated that when PTK6 expression was knocked down by siRNAs, cell proliferation and migration were considerably inhibited in BC cell lines T24 and EJ. By these approaches, we are intended to elucidate PTK6 may be a reliable therapeutic target in BC and might benefit from PTK6 inhibitors in the future.

5.
Nat Commun ; 8(1): 1159, 2017 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-29079782

RESUMO

Autophagy is a degradative pathway that delivers cellular components to the lysosome for degradation. The role of autophagy in cell differentiation is poorly understood. Here we show that CaMKII can directly phosphorylate Beclin 1 at Ser90 to promote K63-linked ubiquitination of Beclin 1 and activation of autophagy. Meanwhile, CaMKII can also promote K63-linked ubiquitination of inhibitor of differentiation 1/2 (Id-1/2) by catalyzing phosphorylation of Id proteins and recruiting TRAF-6. Ubiquitinated Id-1/Id-2 can then bind to p62 and be transported to autolysosomes for degradation. Id degradation promotes the differentiation of neuroblastoma cells and reduces the proportion of stem-like cells. Our study proposes a mechanism by which autophagic degradation of Id proteins can regulate cell differentiation. This suggests that targeting of CaMKII and the regulation of autophagic degradation of Id may be an effective therapeutic strategy to induce cell differentiation in neuroblastoma.


Assuntos
Proteína Beclina-1/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína 1 Inibidora de Diferenciação/metabolismo , Proteína 2 Inibidora de Diferenciação/metabolismo , Neuroblastoma/metabolismo , Animais , Autofagia , Diferenciação Celular , Fibroblastos/metabolismo , Células HEK293 , Humanos , Lisina/química , Lisossomos/metabolismo , Camundongos , Fosforilação , Proteínas de Ligação a RNA/metabolismo , Serina/química , Fator 6 Associado a Receptor de TNF/metabolismo , Ubiquitinação
6.
Oncotarget ; 8(5): 8120-8130, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-28042955

RESUMO

BACKGROUND: To develop and validate a nomogram based on log of odds between the number of positive lymph node and the number of negative lymph node (LODDS) in predicting the overall survival (OS) and cancer specific survival (CSS) for epithelial ovarian cancer (EOC) patients. MATERIALS AND METHODS: A total of 10,692 post-operative EOC patients diagnosed between 2004 and 2013 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into training (n = 7,021) and validation (n = 3,671) cohorts. Multiple clinical pathological parameters were assessed and compared with outcomes. Parameters significantly correlating with outcomes were used to build a nomogram. Bootstrap validation was subsequently used to assess the predictive value of the model. RESULTS: In the training set, age at diagnosis, race, marital status, tumor location, stage, grade and LODDS were correlated significantly with outcome in both the univariate and multivariate analyses and were used to develop a nomogram. The nomogram demonstrated good accuracy in predicting OS and CSS, with a bootstrap-corrected concordance index of 0.757 (95% CI, 0.746-0.768) for OS and 0.770 (95% CI, 0.759-0.782) for CSS. Notably, in this population our model performed favorably compared to the currently utilized Federation of Gynecology and Obstetrics (FIGO) model, with concordance indices of 0.699 (95% CI, 0.688-0.710, P < 0.05) and 0.719 (95% CI, 0.709- 0.730, P < 0.05) for OS and CSS, respectively. Using our nomogram in the validation cohort, the C-indices were 0.757 (95% CI, 0.741-0.773, P < 0.05, compared to FIGO) for OS and 0.762 (95% CI, 0.746-0.779, P < 0.05, compared to FIGO) for CSS. CONCLUSIONS: LODDS works as an independent prognostic factor for predicting survival in patients with EOC regardless of the tumor stage. By incorporating LODDS, our nomogram may be superior to the currently utilized FIGO staging system in predicting OS and CSS among post-operative EOC patients.


Assuntos
Técnicas de Apoio para a Decisão , Linfonodos/patologia , Neoplasias Epiteliais e Glandulares/secundário , Nomogramas , Neoplasias Ovarianas/patologia , Idoso , Área Sob a Curva , Carcinoma Epitelial do Ovário , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfonodos/cirurgia , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Epiteliais e Glandulares/cirurgia , Razão de Chances , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/cirurgia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Programa de SEER , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
7.
Oncotarget ; 6(19): 17491-500, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-26036637

RESUMO

The combination of time and order-dependent chemotherapeutic strategies has demonstrated enhanced efficacy in killing cancer cells while minimizing adverse effects. However, the precise mechanism remains elusive. Our results showed that pre-treatment of MCF-7 and MDA-MB-468 cells with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib or lapatinib significantly enhanced the cytotoxic effects of DNA-damaging agents compared to coadministration of the EGFR inhibitor and DNA-damaging agent. Sequential application of erlotinib and doxorubicin increased activated caspase-8 by promoting pro-caspase-8 homodimerization and autocatalytical cleavage, whereas coadministration did not. We found that EGFR inhibitors promoted pro-caspase-8 homodimerization by inhibiting ERK pathway signaling, while doxorubicin promoted it. Our data highlight that ERK has the potential to inhibit the formation of pro-caspase-8 homodimers by phosphorylating pro-caspase-8 at S387. In conclusion, the pretreatment of EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging agents. Our findings provide rationale for novel strategies for the implementation of combined targeted and cytotoxic chemotherapy within a new framework of time and order-dependent therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Caspase 8/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica , Western Blotting , Linhagem Celular Tumoral , Dano ao DNA , Doxorrubicina/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/administração & dosagem , Humanos , Imunoprecipitação , Lapatinib , Quinazolinas/administração & dosagem , Transfecção
8.
Nat Commun ; 6: 7215, 2015 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-26008601

RESUMO

Beclin 1, a protein essential for autophagy, regulates autophagy by interacting with Vps34 and other cofactors to form the Beclin 1 complex. Modifications of Beclin 1 may lead to the induction, inhibition or fine-tuning of the autophagic response under a variety of conditions. Here we show that Beclin 1 is acetylated by p300 and deacetylated by SIRT1 at lysine residues 430 and 437. In addition, the phosphorylation of Beclin 1 at S409 by CK1 is required for the subsequent p300 binding and Beclin 1 acetylation. Beclin 1 acetylation inhibits autophagosome maturation and endocytic trafficking by promoting the recruitment of Rubicon. In tumour xenografts, the expression of 2KR mutant Beclin 1 (substitution of K430 and K437 to arginines) leads to enhanced autophagosome maturation and tumour growth suppression. Therefore, our study identifies an acetylation-dependent regulatory mechanism governing Beclin 1 function in autophagosome maturation and tumour growth.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Autofagia , Carcinogênese , Proteínas de Membrana/metabolismo , Acetilação , Animais , Proteína Beclina-1 , Caseína Quinase I/metabolismo , Feminino , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células MCF-7 , Camundongos Nus , Fosforilação , Processamento de Proteína Pós-Traducional , Sirtuína 1/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
9.
Oncotarget ; 6(7): 5134-46, 2015 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-25762617

RESUMO

Dual PI3K/mTOR(phosphatidylinositol 3-kinase/mammalian target of rapamycin) inhibitors are being evaluated clinically for the treatment of tumors with a hyperactivated PI3K/mTOR pathway. However, unexpected outcomes were obtained in clinical studies of cancer patients with an aberrant PI3K pathway. In clinical trials, applicable combination regimens are not yet available. In this study, using an integrated analysis of acquired BEZ235-resistant nasopharyngeal carcinoma cells, we demonstrate that DNA methyltransferase is a key modulator and a common node upstream of the AKT/mTOR and PDK1/MYC pathways, which are activated in cancer cells with acquired BEZ235 resistance. DNA methyltransferases were upregulated and induced PTEN and PPP2R2B gene hypermethylation, which downregulated their expression in BEZ235-resistant cancer cells. Reduced PTEN and PPP2R2B expression correlated with activated AKT/mTOR and PDK1/MYC pathways and conferred considerable BEZ235 resistance in nasopharyngeal carcinoma. Targeting methyltransferases in combination with BEZ235 sensitized BEZ235-resistant cells to BEZ235 in vitro and in vivo, suggesting the potential clinical application of this strategy to overcome BEZ235 resistance.


Assuntos
DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Western Blotting , Ciclo Celular , Proliferação de Células , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Feminino , Humanos , Imidazóis/farmacologia , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/genética , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinolinas/farmacologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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