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1.
Polymers (Basel) ; 11(11)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31653001

RESUMO

Impaired growth factor production, angiogenic response, macrophage function, and collagen accumulation have been shown to delay wound healing. Delayed wound healing is a debilitating complication of diabetes that leads to significant morbidity. In this study, curcumin and Lithospermi radix (LR) extract, which are used in traditional Chinese herbal medicine, were added within nanofibrous membranes to improve wound healing in a streptozotocin (STZ)-induced diabetic rat model. Gelatin-based nanofibers, which were constructed with curcumin and LR extract at a flow rate of 0.1 mL/hour and an applied voltage of 20 kV, were electrospun onto chitosan scaffolds to produce bilayer nanofibrous scaffolds (GC/L/C). The wounds treated with GC/L/C exhibited a higher recovery rate and transforming growth factor-beta (TGF-ß) expression in Western blot assays. The decreased levels of pro-inflammatory markers, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), provided evidence for the anti-inflammatory effects of GC/L/C treatment. Chronic wounds treated with GC/L/C achieved better performance with a 58 ± 7% increase in recovery rate on the seventh day. Based on its anti-inflammatory and wound-healing effects, the GC/L/C bilayer nanofibrous scaffolds can be potential materials for chronic wound treatment.

2.
Int J Mol Sci ; 20(19)2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31569723

RESUMO

Although dual EGFR/HER2 tyrosine kinase inhibitor lapatinib has provided effective clinical benefits for HER2-positive breast cancer patients, acquired resistance to this drug remains a major concern. Thus, the development of alternative therapeutic strategies is urgently needed for patients who failed lapatinib treatment. Proteasome inhibitors have been reported to possess high anti-tumor activity to breast cancer cells. Therefore, this study aims to examine whether and how proteasome inhibitor bortezomib can overcome lapatinib resistance. Treatments with several proteasome inhibitors, including Bortezomib, MG132, and proteasome inhibitor I (PSI), as well as the viabilities of both HER2-positive breast cancer cell lines and their lapatinib-resistant clones, were inhibited. Importantly, the expressions of ErbB family were downregulated at both transcriptional and translational levels. Also, our results further indicated that proteasome inhibitors decreased ErbB family expression through lysosomal degradation pathway in a heat shock protein 90 (HSP90)-dependent manner. In this study, our data supported a potential approach to overcome the acquired resistance of HER2-overexpressing breast cancer patients to lapatinib using proteasome inhibitors.

3.
Anticancer Res ; 39(10): 5375-5380, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570432

RESUMO

BACKGROUND/AIM: Matrix metalloproteinases-11 (MMP-11) overexpression has been reported in various types of cancer including lung cancer. We aimed to examine the contribution of MMP-11 genotypes to lung cancer risk. MATERIALS AND METHODS: In this case-control study, the MMP-11 rs738791, rs2267029, rs738792 and rs28382575 genotypes were determined among 358 lung cancer patients and 716 age- and gender-matched healthy control Taiwanese. RESULTS: The percentages of rs738791 CT and TT were 50.6% and 9.2% in the case group, slightly higher than 48.5% and 8.1% in the control group (p for trend=0.5638). The allelic analysis showed that the rs738791 T allele did not confer lung cancer risk compared with the C allele. Similarly, there was no association between rs2267029, rs738792 or rs28382575 and lung cancer risk. There was no joint effect of MMP-11 genotypes among ever smokers or non-smokers. CONCLUSION: The genotypes of MMP-11 play a minor role in determining lung cancer risk in Taiwan.


Assuntos
Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Metaloproteinase 11 da Matriz/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taiwan
4.
Mol Oncol ; 13(9): 1874-1886, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31199048

RESUMO

Sodium/glucose cotransporter 1 (SGLT1), an essential active glucose transport protein that helps maintain high intracellular glucose levels, was previously shown to interact with epidermal growth factor receptor (EGFR); the SGLT1-EGFR interaction maintains intracellular glucose levels to promote survival of cancer cells. Here, we explore the role of SGLT1 in triple-negative breast cancer (TNBC), which is the most aggressive type of breast cancer. We performed TCGA analysis coupled to in vitro experiments in TNBC cell lines as well as in vivo xenografts established in the mammary fat pad of female nude mice. Tissue microarrays of TNBC patients with information of clinical-pathological parameters were also used to investigate the expression and function of SGLT1 in TNBC. We show that high levels of SGLT1 are associated with greater tumour size in TNBC. Knockdown of SGLT1 compromises cell growth in vitro and in vivo. We further demonstrate that SGLT1 depletion results in decreased levels of phospho-EGFR, and as a result, the activity of downstream signalling pathways (such as AKT and ERK) is inhibited. Hence, targeting SGLT1 itself or the EGFR-SGLT1 interaction may provide novel therapeutics against TNBC.

5.
Biochem Pharmacol ; 166: 23-32, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31075265

RESUMO

Lung cancers have a predilection for metastasizing to bone. The matricellular glycoprotein thrombospondin (TSP)-2 regulates multiple biological functions and has a critical role in tumor development and metastasis, although its effects are uncertain in lung cancer bone metastasis. This study demonstrates that TSP-2 expression is highly correlated with lung cancer tumor stage and that the TSP-2 neutralizing antibody reduces osteoclast formation in conditioned medium obtained from lung cancer cells. We also found that TSP-2 promotes osteoclastogenesis through the RANKL-dependent pathway and that TSP-2-mediated osteoclastogenesis involves the transactivation of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) via the inhibition of miR-486-3p expression. Osteoblasts played a critical role in osteoclast differentiation and incubation of osteoblasts with TSP-2 altered the RANKL:OPG ratio. Furthermore, TSP-2 knockdown inhibited lung cancer osteolytic metastasis in vivo. TSP-2 appears to be worth targeting for the prevention of bone metastasis in lung cancer.

6.
Anticancer Res ; 39(2): 721-726, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30711950

RESUMO

BACKGROUND/AIM: Hepatitis B virus-encoded X protein (HBx) plays a pivotal role in hepatocellular carcinoma (HCC) progression and treatment resistance. Interestingly, our previous study unexpectedly showed that full-length HBx sensitized HCC cells to lapatinib by up-regulating erb-b2 receptor tyrosine kinase 3 (ERBB3). We further aimed to map the exact motif within the HBx sequence responsible for lapatinib sensitization. MATERIALS AND METHODS: The exact motif responsible for the lapatinib sensitization was assessed by construction of various fragments of HBx. Cell viability was examined by the MTT assay and crystal violet staining. RESULTS: Our investigation found that lapatinib sensitivity and up-regulation of ERBB3 promoter activity were observed only in HCC cells expressing C-terminal residues of HBx. Furthermore, C-terminal HBx peptide induced ERBB3 protein expression and sensitivity to lapatinib. CONCLUSION: These results not only indicate that the C-terminus of HBx is required for lapatinib sensitivity, but also provide clues to developing a predictive biomarker for response of HCC to lapatinib in the future.


Assuntos
Antivirais/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Lapatinib/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Transativadores/química , Biomarcadores Tumorais/química , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/virologia , Peptídeos/química , Domínios Proteicos , Receptor ErbB-3/metabolismo , Regulação para Cima
7.
Environ Toxicol ; 34(2): 203-209, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30421542

RESUMO

Lung cancer is one of the most common cancer in cancer-related deaths worldwide, which is characterized by its strong metastatic potential. The melatonin hormone secreted by the pineal grand has an antioxidant effect and protects cells against carcinogenic substances. However, the effects of melatonin in lung cancer stemness are largely unknown. We found that melatonin reduces CD133 expression by ~50% in lung cancer cell lines, while results of a sphere formation assay showed that melatonin inhibits lung cancer stemness. These effects of melatonin were reversed when the cell lines were incubated with phospholipase C (PLC), ERK/p38, and a ß-catenin activator. Transfection with Twist siRNA augmented the inhibitory effects of melatonin, indicating that melatonin suppresses lung cancer stemness by inhibiting the PLC, ERK/p38, ß-catenin, and Twist signaling pathways. We also found CD133 expression is positively correlated with Twist expression in lung cancer specimens. Melatonin shows promise in the treatment of lung cancer stemness and deserves further study.


Assuntos
Neoplasias Pulmonares/patologia , Melatonina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células A549 , Antígeno AC133/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição Twist/antagonistas & inibidores , Fosfolipases Tipo C/antagonistas & inibidores , beta Catenina/antagonistas & inibidores
8.
Cancer Cell ; 34(6): 954-969.e4, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30537515

RESUMO

Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of nuclear protein kinase Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Moreover, the level of nuclear PKCδ is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Quinase C-delta/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mutação , Proteína Quinase C-delta/metabolismo , Interferência de RNA
9.
Mol Oncol ; 12(5): 705-723, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29570930

RESUMO

Cigarette smoking is one of the leading risks for lung cancer and is associated with the insensitivity of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, it remains undetermined whether and how cigarette smoke affects the therapeutic efficacy of EGFR TKIs. In this study, our data showed that chronic exposure to cigarette smoke extract (CSE) or tobacco smoke-derived carcinogen benzo[α]pyrene, B[α]P, but not nicotine-derived nitrosamine ketone (NNK), reduced the sensitivity of wild-type EGFR-expressing NSCLC cells to EGFR TKIs. Treatment with TKIs almost abolished EGFR tyrosine kinase activity but did not show an inhibitory effect on downstream Akt and ERK pathways in B[α]P-treated NSCLC cells. CSE and B[α]P transcriptionally upregulate c-MET and activate its downstream Akt pathway, which is not inhibited by EGFR TKIs. Silencing of c-MET reduces B[α]P-induced Akt activation. The CSE-treated NSCLC cells are sensitive to the c-MET inhibitor crizotinib. These findings suggest that cigarette smoke augments oncogene addiction to c-MET in NSCLC cells and that MET inhibitors may show clinical benefits for lung cancer patients with a smoking history.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Oncogenes , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Fumar/efeitos adversos , Benzo(a)pireno , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Modelos Biológicos , Mutação/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
10.
Gastroenterology ; 154(8): 2209-2221.e14, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29454793

RESUMO

BACKGROUND & AIMS: Hepatic stellate cells (HSCs) contribute to desmoplasia and stiffness of liver metastases by differentiating into matrix-producing myofibroblasts. We investigated whether stiffness due to the presence of tumors increases activation of HSCs into myofibroblasts and their tumor-promoting effects, as well as the role of E1A binding protein p300, a histone acetyltransferase that regulates transcription, in these processes. METHODS: HSCs were isolated from liver tissues of patients, mice in which the p300 gene was flanked by 2 loxP sites (p300F/F mice), and p300+/+ mice (controls). The HSCs were placed on polyacrylamide gels with precisely defined stiffness, and their activation (differentiation into myofibroblasts) was assessed by immunofluorescence and immunoblot analyses for alpha-smooth muscle actin. In HSCs from mice, the p300 gene was disrupted by cre recombinase. In human HSCs, levels of p300 were knocked down with small hairpin RNAs or a mutant form of p300 that is not phosphorylated by AKT (p300S1834A) was overexpressed. Human HSCs were also cultured with inhibitors of p300 (C646), PI3K signaling to AKT (LY294002), or RHOA (C3 transferase) and effects on stiffness-induced activation were measured. RNA sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction were used to identify HSC genes that changed expression levels in response to stiffness. We measured effects of HSC-conditioned media on proliferation of HT29 colon cancer cells and growth of tumors following subcutaneous injection of these cells into mice. MC38 colon cancer cells were injected into portal veins of p300F/Fcre and control mice, and liver metastases were measured. p300F/Fcre and control mice were given intraperitoneal injections of CCl4 to induce liver fibrosis. Liver tissues were collected and analyzed by immunofluorescence, immunoblot, and histology. RESULTS: Substrate stiffness was sufficient to activate HSCs, leading to nuclear accumulation of p300. Disrupting p300 level or activity blocked stiffness-induced activation of HSCs. In HSCs, substrate stiffness activated AKT signaling via RHOA to induce phosphorylation of p300 at serine 1834; this caused p300 to translocate to the nucleus, where it up-regulated transcription of genes that increase activation of HSCs and metastasis, including CXCL12. MC38 cells, injected into portal veins, formed fewer metastases in livers of p300F/Fcre mice than control mice. Expression of p300 was increased in livers of mice following injection of CCl4; HSC activation and collagen deposition were reduced in livers of p300F/Fcre mice compared with control mice. CONCLUSIONS: In studies of mice, we found liver stiffness to activate HSC differentiation into myofibroblasts, which required nuclear accumulation of p300. p300 increases HSC expression of genes that promote metastasis.


Assuntos
Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/metabolismo , Proteína p300 Associada a E1A/metabolismo , Células Estreladas do Fígado/patologia , Neoplasias Hepáticas/patologia , Miofibroblastos/patologia , Animais , Benzoatos/farmacologia , Tetracloreto de Carbono/toxicidade , Núcleo Celular/metabolismo , Transdiferenciação Celular , Proteína p300 Associada a E1A/genética , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HT29 , Células Estreladas do Fígado/metabolismo , Humanos , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Camundongos , Camundongos Knockout , Camundongos SCID , Miofibroblastos/metabolismo , Fosforilação , Cultura Primária de Células , Pirazóis/farmacologia , RNA Interferente Pequeno/antagonistas & inibidores , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína rhoA de Ligação ao GTP/metabolismo
11.
Am J Cancer Res ; 8(12): 2575-2589, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30662813

RESUMO

Incense burning is common in Asian countries due to the religious beliefs. Environmental exposure to incense burning smoke is a potential risk factor for tumor development and progression of non-small cell lung cancer (NSCLC). Eastern Asia ethnic origin is strongly associated the clinical benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC patients. However, the impact of the oriental custom of incense burning on the cancer progression and the EGFR TKI-sensitivity of NSCLC remains unclear. Our results showed that long-term exposure to incense burning extract (IBE) increases the cellular proliferation with S phase accumulation and the motility activity of NSCLCs. Interestingly, IBE enhances EGFR signaling activity without affecting its genetic status, and increases the cellular sensitivity of NSCLC cell lines to EGFR TKIs. Auramine, a yellow dye for making incense sticks, was identified as a residual composition in the burning incense smoke, and showed similar EGFR TKI-sensitizing effects. Furthermore, IBE or auramine transcriptionally induce EGFR ligand amphiregulin (AREG) expression for the enhancement of EGFR activity. Neutralization of AREG reduced the viability of IBE-treated cells. These results indicated that exposure to incent smoke may enhance NSCLC progression and their sensitivity to EGFR TKIs through increasing their oncogenic addiction to AREG-induced EGFR signaling.

12.
Environ Toxicol ; 32(11): 2379-2391, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28722353

RESUMO

Burning incense to worship deities is a popular religious ritual in large parts of Asia, and is a popular custom affecting more than 1.5 billion adherents. Due to incomplete combustion, burning incense has been well recognized to generate airborne hazards to human health. However, the correlation between burning incense and lung cancer in epidemiological studies remains controversy. Therefore, we speculated that some unknown materials in incense smoke are involved in the initiation or progression of lung cancer. Based on this hypothesis, we identified a major compound auramine O (AuO) from the water-soluble fraction of incense burned condensate using mass spectrometry. AuO is commonly used in incense manufacture as a colorant. Due to thermostable, AuO released from burned incenses becomes an unexpected air pollutant. AuO is classified as a Group 2B chemical by the International Agency of Research on Cancer (IARC), however, the damage of AuO to the respiratory system remains elusive. Our study revealed that AuO has no apparent effect on malignant transformation; but, it dramatically promotes lung cancer malignancy. AuO accumulates in the nucleus and induces the autophagy activity in lung tumor cells. AuO significantly enhances migration and invasive abilities and the in vitro and in vivo stemness features of lung tumor cells through activating the expression of aldehyde dehydrogenase family 1 member A1 (ALDH1A1), and ALDH1A1 knockdown attenuates AuO-induced autophagy activity and blocks AuO-induced lung tumor malignancy. In conclusion, we found that AuO, an ingredient of incense smoke, significantly increases the metastatic abilities and stemness characters of lung tumor cells through the activation of ALDH1A1, which is known to be associated with poor outcome and progression of lung cancer. For public health, reducing or avoiding the use of AuO in incense is recommended.


Assuntos
Adenocarcinoma/patologia , Poluentes Atmosféricos/toxicidade , Benzofenoneídio/toxicidade , Corantes/toxicidade , Neoplasias Pulmonares/patologia , Fumaça/efeitos adversos , Adenocarcinoma/induzido quimicamente , Adenocarcinoma de Pulmão , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Animais , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Neoplasias Pulmonares/induzido quimicamente , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Retinal Desidrogenase , Fumaça/análise , Esferoides Celulares/patologia
13.
Mol Oncol ; 11(9): 1273-1287, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28632938

RESUMO

Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2-positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase-dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin-dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK-mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor-induced Akt activation.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Retroalimentação Fisiológica , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Fosfotreonina/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Sequência de Aminoácidos , Linhagem Celular Tumoral , Clatrina/metabolismo , Regulação para Baixo , Endocitose/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Ligação Proteica , Multimerização Proteica/efeitos dos fármacos , Receptor ErbB-2/química
14.
Oncotarget ; 7(38): 62352-62363, 2016 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-27694691

RESUMO

Lapatinib is an inhibitor of human epidermal growth factor receptor 2 (HER2), which is overexpressed in 20-25% of breast cancers. Clinically, lapatinib has shown promising benefits for HER2-positive breast cancer patients; however, patients eventually acquire resistance, limiting its long-term use. In a previous study, we found that interleukin-6 (IL-6) production was increased in acquired lapatinib-resistant HER2-positive breast cancer cells. In the present study, we confirmed that lapatinib-resistant cells had elevated IL-6 expression and also maintained both stemness population and property. The increase in IL-6 was required for stemness property maintenance, which was mediated primarily through the activation of signal transducer and activator of transcription 3 (STAT3). Blocking IL-6 activity reduced spheroid formation, cell viability and subsequently overcame lapatinib resistance, whereas stimulation of IL-6 rendered parental cells more resistant to lapatinib-induced cytotoxicity. These results point to a novel mechanism underlying lapatinib resistance and provide a potential strategy to overcome resistance via IL-6 inhibition.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Interleucina-6/metabolismo , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-6/genética , Lapatinib , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais , Esferoides Celulares , Regulação para Cima
15.
Oncotarget ; 7(35): 56309-56323, 2016 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-27409165

RESUMO

Maspin is a tumor suppressor that stimulates apoptosis and inhibits metastasis in various cancer types, including hepatocellular carcinoma (HCC). Our previous study has demonstrated that HBx induced microRNA-7, 103, 107, and 21 expressions to suppress maspin expression, leading to metastasis, chemoresistance, and poor prognosis in HCC patients. However, it remains unclear how HBx elicits these microRNA expressions. HBx has been known to induce aberrant activation and nuclear translocation of inhibitor-κB kinase-α (IKKα) to promote HCC progression. In this study, our data further revealed that nuclear IKKα expression was inversely correlated with maspin expression in HBV-associated patients. Nuclear IKKα but not IKKß reduced maspin protein and mRNA expression, and inhibition of IKKα reverses HBx-mediated maspin downregulation and chemoresistance. In response to HBx overexpression, nuclear IKKα was further demonstrated to induce the gene expressions of microRNA-7, -103, -107, and -21 by directly targeting their promoters, thereby leading to maspin downregulation. These findings indicated nuclear IKKα as a critical regulator for HBx-mediated microRNA induction and maspin suppression, and suggest IKKα as a promising target to improve the therapeutic outcome of HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Vírus da Hepatite B/fisiologia , Quinase I-kappa B/metabolismo , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , Serpinas/metabolismo , Transativadores/genética , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Progressão da Doença , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Genes Supressores de Tumor , Células HEK293 , Histonas/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serpinas/genética , Transdução de Sinais , Transativadores/metabolismo
16.
Am J Cancer Res ; 6(4): 747-63, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27186428

RESUMO

We investigated the anticancer potential of a new synthetic compound, 7-(3-fluorophenyl)-4-methylpyrido-[2,3-d]pyrimidin-5(8H)-one (MT3-037). We found that MT3-037 effectively decreased the cancer cell viability by inducing apoptosis. MT3-037 treatments led to cell cycle arrest at M phase, with a marked increase in both expression of cyclin B1 and cyclin-dependent kinase 1 (CDK1) as well as in CDK1 kinase activity. Key proteins that regulate mitotic spindle dynamics, including survivin, Aurora A/B kinases, and polo-like kinase 1 (PLK1), were activated in MT3-037-treated cells. MT3-037-induced apoptosis was accompanied by activation of a pro-apoptotic factor, FADD, and the inactivation of apoptosis inhibitors, Bcl-2 and Bcl-xL, resulting in the cleavage/activation of caspases. The activation of c-Jun N-terminal kinase (JNK) was associated with MT3-037-induced CDK1 and Aurora A/B activation and apoptosis. Immunofluorescence staining of tubulin indicated that MT3-037 altered tubulin networks in cancer cells. Moreover, an in vitro tubulin polymerization assay revealed that MT3-037 inhibited the tubulin polymerization by direct binding to tubulin. Molecular docking studies and binding site completion assays revealed that MT3-037 binds to the colchicine-binding site. Furthermore, MT3-037 significantly inhibited the tumor growth in both MDAMB-468 and Erlotinib-resistant MDA-MB-468 xenograft mouse models. In addition, MT3-037 inhibited the angiogenesis and disrupted the tube formation by human endothelial cells. Our study demonstrates that MT3-037 is a potential tubulin-disrupting agent for antitumor therapy.

17.
Oncotarget ; 7(1): 473-89, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26595522

RESUMO

Poor prognosis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) involves HBV X protein (HBx)-induced tumor progression. HBx also contributes to chemo-resistance via inducing the expressions of anti-apoptosis and multiple drug resistance genes. However, the impact of HBx expression on the therapeutic efficacy of various receptor tyrosine kinase inhibitors remains unknown. In this study, our data showed that HBx overexpression did not alter the cellular sensitivity of HCC cell lines to sorafenib but unexpectedly enhanced the cell death induced by EGFR family inhibitors, including gefitinib, erlotinib, and lapatinib due to ErbB3 up-regulation. Mechanistically, HBx transcriptionally up-regulates ErbB3 expression in a NF-κB dependent manner. In addition, HBx also physically interacts with ErbB2 and ErbB3 proteins and enhances the formation of ErbB2/ErbB3 heterodimeric complex. The cell viability of HBx-overexpressing cells was decreased by silencing ErbB3 expression, further revealing the pivotal role of ErbB3 in HBx-mediated cell survival. Our data suggest that HBx shifts the oncogenic addiction of HCC cells to ErbB2/ErbB3 signaling pathway via inducing ErbB3 expression and thereby enhances their sensitivity to EGFR/ErbB2 inhibitors.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Quinazolinas/farmacologia , Receptor ErbB-3/metabolismo , Transativadores/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Humanos , Lapatinib , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , NF-kappa B/genética , NF-kappa B/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genética , Regulação para Cima/efeitos dos fármacos
18.
J Thorac Dis ; 8(11): E1475-E1477, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28066635
19.
Oncotarget ; 6(35): 37965-78, 2015 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-26513016

RESUMO

Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3'UTR activity, and that down-regulation of miR-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of miR7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression.


Assuntos
Movimento Celular/efeitos dos fármacos , Interleucina-6/metabolismo , MicroRNAs/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Quinazolinas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Antineoplásicos/farmacologia , Western Blotting , Proliferação de Células/efeitos dos fármacos , Imunoprecipitação da Cromatina , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Interleucina-6/genética , Lapatinib , Proteína Quinase 1 Ativada por Mitógeno/genética , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-raf/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Células Tumorais Cultivadas
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