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1.
Lab Invest ; 102(7): 741-752, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35351965

RESUMO

Invasive growth of glioblastoma makes residual tumor unremovable by surgery and leads to disease relapse. Temozolomide is widely used first-line chemotherapy drug to treat glioma patients, but development of temozolomide resistance is almost inevitable. Ferroptosis, an iron-dependent form of non-apoptotic cell death, is found to be related to temozolomide response of gliomas. However, whether inducing ferroptosis could affect invasive growth of glioblastoma cells and which ferroptosis-related regulators were involved in temozolomide resistance are still unclear. In this study, we treated glioblastoma cells with RSL3, a ferroptosis inducer, in vitro (cell lines) and in vivo (subcutaneous and orthotopic animal models). The treated glioblastoma cells with wild-type or mutant IDH1 were subjected to RNA sequencing for transcriptomic profiling. We then analyze data from our RNA sequencing and public TCGA glioma database to identify ferroptosis-related biomarkers for prediction of prognosis and temozolomide resistance in gliomas. Analysis of transcriptome data from RSL3-treated glioblastoma cells suggested that RSL3 could inhibit glioblastoma cell growth and suppress expression of genes involved in cell cycle. RSL3 effectively reduced mobility of glioblastoma cells through downregulation of critical genes involved in epithelial-mesenchymal transition. Moreover, RSL3 in combination with temozolomide showed suppressive efficacy on glioblastoma cell growth, providing a promising therapeutic strategy for glioblastoma treatment. Although temozolomide attenuated invasion of glioblastoma cells with mutant IDH1 more than those with wild-type IDH1, the combination of RSL3 and temozolomide similarly impaired invasive ability of glioblastoma cells in spite of IDH1 status. Finally, we noticed that both ferritin heavy chain 1 and ferritin light chain predicted unfavorable prognosis of glioma patients and were significantly correlated with mRNA levels of methylguanine methyltransferase as well as temozolomide resistance. Altogether, our study provided rationale for combination of RSL3 with temozolomide to suppress glioblastoma cells and revealed ferritin heavy chain 1 and ferritin light chain as biomarkers to predict prognosis and temozolomide resistance of glioma patients.


Assuntos
Neoplasias Encefálicas , Ferroptose , Glioblastoma , Glioma , Animais , Apoferritinas/farmacologia , Apoferritinas/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Temozolomida/farmacologia , Temozolomida/uso terapêutico
2.
Lab Invest ; 100(6): 812-823, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31949244

RESUMO

Glioblastoma multiforme (GBM) is characterized by highly invasive growth, which leads to extensive infiltration and makes complete tumor excision difficult. Since cytoskeleton proteins are related to leading processes and cell motility, and through analysis of public GBM databases, we determined that an actin-interacting protein, zyxin (ZYX), may involved in GBM invasion. Our own glioma cohort as well as the cancer genome atlas (TCGA), Rembrandt, and Gravendeel databases consistently showed that increased ZYX expression was related to tumor progression and poor prognosis of glioma patients. In vitro and in vivo experiments further confirmed the oncogenic roles of ZYX and demonstrated the role of ZYX in GBM invasive growth. Moreover, RNA-seq and mass-spectrum data from GBM cells with or without ZYX revealed that stathmin 1 (STMN1) was a potential target of ZYX. Subsequently, we found that both mRNA and protein levels of STMN1 were positively regulated by ZYX. Functionally, STMN1 not only promoted invasion of GBM cells but also rescued the invasion repression caused by ZYX loss. Taken together, our results indicate that high ZYX expression was associated with worse prognosis and highlighted that the ZYX-STMN1 axis might be a potential therapeutic target for GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Invasividade Neoplásica/patologia , Zixina , Animais , Biomarcadores Tumorais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Técnicas de Silenciamento de Genes , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Humanos , Camundongos , Camundongos Endogâmicos NOD , Prognóstico , Estatmina/análise , Estatmina/genética , Estatmina/metabolismo , Zixina/análise , Zixina/genética , Zixina/metabolismo
3.
Ultrastruct Pathol ; 38(5): 329-34, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25079492

RESUMO

To investigate the effect of ritonavir on hepatocyte proliferation, we detected the change of cleaved caspase-3 expression level in the hepatocytes. Furthermore, the morphological and ultrastructural changes of hepatocytes derived from RTV-treated mice have been observed. The results showed that ritonavir can evidently inhibit hepatocyte proliferation and increase cleaved caspase-3 expression level. Under the electron microscope, chromatin margination, mitochondrial cristae disappearance, karyopyknosis and cytoplasmic vacuolization can be observed in the hepatocytes of mice treated with ritonavir. In conclusion, the mechanism of ritonavir's hepatotoxicity is that it induces apoptosis of hepatocytes via the caspase-cascade system.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Ritonavir/farmacologia , Animais , Proliferação de Células/fisiologia , Células Cultivadas , Feminino , Hepatócitos/enzimologia , Humanos , Camundongos
4.
Ultrastruct Pathol ; 38(3): 211-6, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24625130

RESUMO

To investigate the effects of X-ray irradiation on the proliferation and apoptosis of MCF-7 breast cancer cells; MCF-7 breast cancer cells were irradiated with X-ray. After irradiation, morphological changes and growth inhibition rate of the irradiated cells were observed under an inverted microscope. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to assess the proliferation of the irradiated MCF-7 cells. Transmission electron microscope was used to observe the morphology and ultrastructure of the irradiated MCF-7 cells. Western blotting was used to analyze the expression level of apoptosis-related protein caspase-3. Our results showed, at 48 h after the irradiation (0 Gy and 8 Gy), cells oval in shape, cell shrinkage or swelling and partial formation of debris under inverted microscope; as well as cytoplasmic vacuolization or inspissation, increased electron density of cytoplasm, structural damage of organelles, blurred mitochondrial cristae and chromatin margination under transmission electron microscopy; the survival rate of MCF-7 cells in X-ray group was 17.3% lower than that in control group (0 Gy) (p < 0.001); while caspase-3 expression increased evidently in X-ray group compared with control group (0 Gy) (p < 0.05). In conclusion, X-ray irradiation can inhibit the proliferation of MCF-7 cells and induce apoptosis through increasing caspase-3 expression.


Assuntos
Apoptose/efeitos da radiação , Neoplasias da Mama/ultraestrutura , Proliferação de Células/efeitos da radiação , Raios X , Neoplasias da Mama/metabolismo , Caspase 3/metabolismo , Forma Celular/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Feminino , Humanos , Células MCF-7 , Microscopia Eletrônica de Transmissão , Fatores de Tempo
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