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2.
PLoS One ; 11(1): e0147157, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26784960

RESUMO

Developing drugs that can effectively block STAT3 activation may serve as one of the most promising strategy for cancer treatment. Currently, there is no putative STAT3 inhibitor that can be safely and effectively used in clinic. In the present study, we investigated the potential of dihydroartemisinin (DHA) as a putative STAT3 inhibitor and its antitumor activities in head and neck squamous cell carcinoma (HNSCC). The inhibitory effects of DHA on STAT3 activation along with its underlying mechanisms were studied in HNSCC cells. The antitumor effects of DHA against HNSCC cells were explored both in vitro and in vivo. An investigation on cooperative effects of DHA with cisplatin in killing HNSCC cells was also implemented. DHA exhibited remarkable and specific inhibitory effects on STAT3 activation via selectively blocking Jak2/STAT3 signaling. Besides, DHA significantly inhibited HNSCC growth both in vitro and in vivo possibly through induction of apoptosis and attenuation of cell migration. DHA also synergized with cisplatin in tumor inhibition in HNSCC cells. Our findings demonstrate that DHA is a putative STAT3 inhibitor that may represent a new and effective drug for cancer treatment and therapeutic sensitization in HNSCC patients.


Assuntos
Artemisininas/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Células Tumorais Cultivadas , Cicatrização , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Oncol Lett ; 7(3): 685-692, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24527073

RESUMO

Hypoxia renders tumor cells with reduced sensitivity and increased resistance to chemotherapeutic agents. One of the possible mechanisms underlying this unfavorable status is activation of the unfolded protein response (UPR) under hypoxic conditions, due to the upregulation of glucose-regulated protein 78 (GRP78) expression. GRP78, an endoplasmic reticulum chaperone protein and a key regulator of the UPR, has been reported to be overexpressed in various types of cancer. However, the role of GRP78 in regulating the cell growth and apoptosis of hypopharyngeal carcinoma cells, with regard to the severity of hypoxia, remains unclear. Therefore, the aim of the present study was to investigate whether, and under what circumstances, GRP78 is associated with hypoxia-induced chemoresistance in hypopharyngeal carcinoma. For this purpose, cells from the FaDu human hypopharyngeal carcinoma cell line were cultured under normoxic and hypoxic conditions for different time periods. No significant changes in GRP78 and C/EBP homology protein (CHOP) protein expression levels were revealed under moderately hypoxic conditions (oxygen concentration, 1%), but these levels were changed over time under severely hypoxic conditions (oxygen concentration, <0.02%). This indicated that severe hypoxia, rather than moderate hypoxia, leads to UPR activation in hypopharyngeal carcinoma cells. Knockdown of GRP78 with short hairpin RNA inhibited cell proliferation and promoted apoptosis under severely hypoxic conditions, even with cisplatin treatment, indicating that GRP78 confers FaDu cells resistant to chemotherapy in response to severe hypoxia. Furthermore, knockdown of GRP78 resulted in a significant increase in CHOP and Bax expression levels and a decrease in Bcl-2 expression levels with simultaneous increase in the levels of apoptosis under severely hypoxic conditions. It was concluded that severe hypoxia leads to UPR activation and elevation of GRP78 expression, promoting cell survival and inducing chemoresistance. Silencing of GRP78 may block the pro-survival arm of UPR, simultaneously promoting proapoptotic signaling through induction of CHOP. Downregulation of GRP78 may be a promising strategy for overcoming the resistance of hypopharyngeal cancer to chemotherapy.

4.
Mol Med Rep ; 6(6): 1418-22, 2012 12.
Artigo em Inglês | MEDLINE | ID: mdl-22971798

RESUMO

The present study evaluated the regulation of glucose transporter protein-1 (Glut-1) and vascular endothelial growth factor (VEGF) by hypoxia inducible factor 1α (HIF-1α) under hypoxic conditions in Hep-2 human cells to explore the feasibility of these three genes as tumor markers. Hep-2 cells were cultured under hypoxic and normoxic conditions for 6, 12, 24, 36 and 48 h. The proliferation of Hep-2 cells was evaluated using an MTT assay. The protein and mRNA expression levels of HIF-1α, Glut-1 and VEGF were detected using the S-P immunocytochemical method, western blotting and reverse transcription polymerase chain reaction (RT-PCR). The results revealed that the expression levels of HIF-1α, Glut-1 and VEGF protein in Hep-2 cells were significantly elevated under hypoxic conditions compared with those under normoxic conditions over 36 h. Under hypoxic conditions, mRNA levels of HIF-1α were stable, while mRNA levels of Glut-1 and VEGF changed over time. In conclusion, Glut-1 and VEGF were upregulated by HIF-1α under hypoxic conditions in a time-dependent manner in Hep-2 cells and their co-expression serves as a tumor marker.


Assuntos
Hipóxia Celular , Transportador de Glucose Tipo 1/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Linhagem Celular Tumoral , Transportador de Glucose Tipo 1/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imuno-Histoquímica , RNA Mensageiro/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética
5.
Artigo em Chinês | MEDLINE | ID: mdl-18950011

RESUMO

OBJECTIVE: To show that Stat3 played a key role in the G1 to S phase transition in laryngocarcinoma cells. METHOD: Human laryngocarcinoma cell lines Hep-2 were transfected with Stat3 antisense oligonucleotide mediated by liposome, MTT assay was used to measure the proliferation, flow cytometry was applied to analyze the cell cycle, and the expressions of Stat3, phosphorylation specific Stat3 (tyrosine705), CyclinD1, Cyclin E, CDK2, CDK4, CDK6, p21 and p27 were detected by western blot. RESULT: Hep-2 laryngocarcinoma cell lines expressed constitutively activated Stat3. Antisense oligonucleotide which directed blocked up the translation site resulted in growth inhibition, downregulation of Stat3, p-Stat3, Cyclins and CDKs, and upregulation of p21 and p27. CONCLUSION: Our findings suggested that Stat3 played an important role in the G1 to S phase transition in laryngocarcinoma cells, Stat3 orchestrated cell cycle by regulating the balance between CDK/Cyclin complex and CKI.


Assuntos
Fase G1 , Neoplasias Laríngeas/metabolismo , Fase S , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Humanos , Neoplasias Laríngeas/patologia , Fator de Transcrição STAT3/genética , Transfecção
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