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1.
Oncol Rep ; 43(2): 591-600, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894331

RESUMO

Mutation of the p53 tumor suppressor frequently occurs in lung cancer, and can be as high as 75­90% in small­cell lung cancer. Mutant p53 (mtp53) can inhibit the wild­type p53 protein, disrupting its tumor suppressor functions. In addition, mutant p53 often acquires the functions of an oncogene. Post­translational modification of the p53 protein is important for its transcriptional and tumor suppressive functions. We previously revealed that high levels of mutant p53 expression were associated with reduced expression of the deacetylation enzyme sirtuin 3 (SIRT3) in lung cancer tissues. Given this negative correlation between p53 and SIRT3 expression, and given that SIRT3 is a deacetylase, we speculated that SIRT3 participates in the post­translational modification of mutant p53, regulating its stability and function, thereby inhibiting the growth of lung cancer cells. Light microscopy, MTT and flow cytometric assays revealed that SIRT3 overexpression inhibited growth and promoted apoptosis in NCI­H446 human small cell lung cancer cells. SIRT3 overexpression also resulted in necroptosis, and this could be partially reversed following cell treatment with the necroptosis inhibitor necrostatin­1 (Nec­1), which could restore certain cells to survive. Western blotting assays revealed that SIRT3 overexpression resulted in the reduced expression and half­life of mutant p53, indicating that SIRT3 decreases mutant p53 stability. Proteasome inhibitor experiments revealed that the decrease in mutant p53 stability was a result of increased proteasomal degradation of the protein. Immunoprecipitation studies revealed that ubiquitination of mutant p53 was elevated in SIRT3­overexpressing cells, indicating that SIRT3 affected ubiquitination­mediated protein degradation. In the present study, it was therefore revealed that SIRT3 can inhibit the growth of human small­cell lung cancer cells by promoting apoptosis and necroptosis. It was also revealed that SIRT3 expression could regulate the stability of mutant p53 by controlling ubiquitination­mediated proteasomal degradation of the protein. SIRT3 expression may therefore play an important role in the growth of mutant p53­associated lung cancer.

2.
Front Aging Neurosci ; 11: 313, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31780922

RESUMO

Neurodegenerative diseases are disorders that are characterized by a progressive decline of motor and/or cognitive functions caused by the selective degeneration and loss of neurons within the central nervous system. The most common neurodegenerative diseases are Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Neurons have high energy demands, and dysregulation of mitochondrial quality and function is an important cause of neuronal degeneration. Mitochondrial quality control plays an important role in maintaining mitochondrial integrity and ensuring normal mitochondrial function; thus, defects in mitochondrial quality control are also significant causes of neurodegenerative diseases. The mitochondrial deacetylase SIRT3 has been found to have a large effect on mitochondrial function. Recent studies have also shown that SIRT3 has a role in mitochondrial quality control, including in the refolding or degradation of misfolded/unfolded proteins, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis, all of which are affected in neurodegenerative diseases.

3.
Cell Biosci ; 9: 52, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31391918

RESUMO

Pyruvate kinase (PK), as one of the key enzymes for glycolysis, can encode four different subtypes from two groups of genes, although the M2 subtype PKM2 is expressed mainly during embryonic development in normal humans, and is closely related to tissue repair and regeneration, with the deepening of research, the role of PKM2 in tumor tissue has received increasing attention. PKM2 can be aggregated into tetrameric and dimeric forms, PKM2 in the dimer state can enter the nuclear to regulate gene expression, the transformation between them can play an important role in tumor cell energy supply, epithelial-mesenchymal transition (EMT), invasion and metastasis and cell proliferation. We will use the switching effect of PKM2 in glucose metabolism as the entry point to expand and enrich the Warburg effect. In addition, PKM2 can also regulate each other with various proteins by phosphorylation, acetylation and other modifications, mediate the different intracellular localization of PKM2 and then exert specific biological functions. In this paper, we will illustrate each of these points.

4.
Cell Biosci ; 9: 59, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31347610

RESUMO

[This corrects the article DOI: 10.1186/s13578-019-0317-8.].

6.
Front Genet ; 10: 531, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275351

RESUMO

Background: Diabetic retinopathy (DR) is a common diabetes complication and was considered as the major cause of blindness among young adults. MiRNAs are a group of small non-coding RNAs regulating the expression of target genes and have been reported to be associated with the development of DR in a variety of molecular mechanisms. In this study, we aimed to identify miRNAs that are differentially expressed (DE) in the serum of DR patients. Methods: We recruited 21 type 2 diabetes mellitus (T2DM) inpatients of Chinese Han ancestry, consisting of 10 non-proliferative DR patients (DR group) and 11 non-DR T2DM patients (NDR group). MiRNA was extracted from fasting peripheral serum and quantified by RNA-seq. The expression levels of miRNA were evaluated and compared between the two groups, with adjustments made for age differences. The validated target genes of miRNAs were subjected to a pathway analysis. We also constructed a weighted polygenic risk score using the DE miRNA and evaluated its predictive power. Results: Five miRNAs were DE between DR and NDR groups (p-Value ≤ 0.01, LFC ≥ 2 or LFC ≤-2). These included miR-4448, miR-338-3p, miR-190a-5p, miR-485-5p, and miR-9-5p. In total, these miRNAs were validated to regulate 55 target genes. Four target genes were found to overlap with the NAD metabolism, sirtuin, and aging pathway, which was thought to control the vascular growth and morphogenesis. The predictive power of our polygenic risk score was apparently high (AUC = 0.909). However, it needs to be interpreted with caution. Conclusion: In this study, we discovered novel DR-specific miRNAs in human serum samples. These circulating miRNAs may represent the pathological changes in the retina in response to diabetes and may serve as non-invasive biomarkers for early DR risk prediction.

7.
Cell Prolif ; 52(3): e12609, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31033054

RESUMO

OBJECTIVES: The genotoxicity of cisplatin towards nuclear DNA is not sufficient to explain the cisplatin resistance of hepatocellular carcinoma (HCC) cells; cisplatin interacts with many organelles, which can influence the sensitivity. Here, we explored the role of mitochondrial-lysosomal crosstalk in the cisplatin resistance of HCC cells. MATERIALS AND METHODS: Huh7 and HepG2 cells were subjected to different treatments. Flow cytometry was conducted to detect mitochondrial reactive oxygen species, mitochondrial mass, lysosomal function, mitochondrial membrane potential and apoptosis. Western blotting was performed to evaluate protein levels. The oxygen consumption rate was measured to evaluate mitochondrial function. RESULTS: Cisplatin activated mitophagy and lysosomal biogenesis, resulting in crosstalk between mitochondria and lysosomes and cisplatin resistance in HCC cells. Furthermore, a combination of cisplatin with the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor PKI-402 induced lysosomal membrane permeabilization. This effect changed the role of the lysosome from a protective one to that of a cell death promoter, completely destroying the mitochondrial-lysosomal crosstalk and significantly enhancing the sensitivity of HCC cells to cisplatin. CONCLUSIONS: This is the first evidence of the importance of mitochondrial-lysosomal crosstalk in the cisplatin resistance of HCC cells and of the destruction of this crosstalk by a PI3K/mTOR inhibitor to increase the sensitivity of HCC cells to cisplatin. This mechanism could be developed as a novel target for treatment of HCC in the future.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Cisplatino/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Células Hep G2 , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo
8.
Cancer Med ; 8(5): 2462-2473, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30972978

RESUMO

Metabolic reprogramming is a central hallmark of cancer. Therefore, targeting metabolism may provide an effective strategy for identifying promising drug targets for cancer treatment. In prostate cancer, cells undergo metabolic transformation from zinc-accumulating, citrate-producing cells to citrate-oxidizing malignant cells with lower zinc levels and higher mitochondrial aconitase (ACO2) activity. ACO2 is a Krebs cycle enzyme that converts citrate to isocitrate and is sensitive to reactive oxygen species (ROS)-mediated damage. In this study, we found that the expression of ACO2 is positively correlated with the malignancy of prostate cancer. Both zinc and p53 can lead to an increase in ROS. ACO2 can be a target for remodeling metabolism by sensing changes in the ROS levels of prostate cancer. Our results indicate that targeting ACO2 through zinc and p53 can change prostate cancer metabolism, and thus provides a potential new therapeutic strategy for prostate cancer.

9.
J Cell Mol Med ; 23(6): 4030-4042, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30941888

RESUMO

Increasing evidence suggests that p62/SQSTM1 functions as a signalling centre in cancer. However, the role of p62 in tumour development depends on the interacting factors it recruits and its precise regulatory mechanism remains unclear. In this study, we investigated the pro-death signalling recruitment of p62 with the goal of improving anti-tumour drug effects in ovarian cancer treatment. We found that p62 with Caspase 8 high expression is correlated with longer survival time compared with cases of low Caspase 8 expression in ovarian cancer. In vivo experiments suggested that insoluble p62 and ubiquitinated protein accumulation induced by autophagy impairment promoted the activation of Caspase 8 and increased cell sensitivity to cisplatin. Furthermore, p62 functional domain UBA and LIR mutants regulated autophagic flux and attenuated Caspase 8 activation, which indicates that autophagic degradation is involved in p62-mediated activation of Caspase 8 in ovarian cancer cells. Collectively, our study demonstrates that p62 promotes Caspase 8 activation through autophagy flux blockage with cisplatin treatment. We have provided evidence that autophagy induction followed by its blockade increases cell sensitivity to chemotherapy which is dependent on p62-Caspase 8 mediated apoptosis signalling. p62 exhibits pro-death functions through its interaction with Caspase 8. p62 and Caspase 8 may become novel prognostic biomarkers and oncotargets for ovarian cancer treatment.

10.
Front Immunol ; 10: 127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774633

RESUMO

The polarization and function of macrophages play essential roles in controlling immune responses. Interleukin (IL)-33 is a member of the IL-1 family that has been shown to influence macrophage activation and polarization, but the underlying mechanisms are not fully understood. Mitochondrial metabolism has been reported to be a central player in shaping macrophage polarization; previous studies have shown that both aerobic glycolysis and oxidative phosphorylation uniquely regulate the functions of M1 and M2 macrophages. Whether IL-33 polarizes macrophages by reshaping mitochondrial metabolism requires further investigation. In this work, we examined the mitochondrial metabolism of bone marrow-derived macrophages (BMDMs) from either wild type (WT), Il33-overexpressing, or IL-33 receptor knockout (St2 -/-) mice challenged with lipopolysaccharide (LPS). We found that after LPS stimulation, compared with WT BMDMs, St2 -/- BMDMs had reduced cytokine production and increased numbers and activity of mitochondria via the metabolism regulator peroxisome proliferator-activated receptor-C coactivator-1 α (PGC1α). This was demonstrated by increased mitochondrial DNA copy number, mitochondria counts, mitochondria fission- and fusion-related gene expression, oxygen consumption rates, and ATP production, and decreased glucose uptake, lactate production, and extracellular acidification rates. For Il33-overexpressing BMDMs, the metabolic reprogramming upon LPS stimulation was similar to WT BMDMs, and was accompanied by increased M1 macrophage activity. Our findings suggested that the pleiotropic IL-33/ST2 pathway may influence the polarization and function of macrophages by regulating mitochondrial metabolism.


Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/genética , Macrófagos/imunologia , Mitocôndrias/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , DNA Mitocondrial/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais
11.
Prostate ; 79(6): 647-656, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30714183

RESUMO

BACKGROUND: Paclitaxel (PTX) is a first-line chemotherapeutic drug for the treatment of prostate cancer. However, most patients develop resistance and metastasis, and thus new therapeutic approaches are urgently required. Recent studies have identified widespread anti-tumor effects of zinc (Zn) in various tumor cell lines, especially prostate cancer cells. In this study, we examined the effects of Zn as an adjuvant to PTX in prostate cancer cells. METHODS: PC3 and DU145 cells were treated with different concentrations of Zn and/or PTX. MTT assay was used to detect cell viability. Real-time cell analysis (RTCA) and microscopy were used to observe morphological changes in cells. Western blotting was used to detect the expression of epithelial-mesenchymal transition (EMT)-related proteins. qPCR (reverse transcription-polymerase chain reaction) was used to examine changes in TWIST1 mRNA levels. Cell invasion and migration were detected by scratch and transwell assays. shRNA against TWIST1 was used to knockdown TWIST1. Colony formation assay was used to detect cell proliferation, while Annexin V and propidium iodide (PI) staining was used to detect cell apoptosis. RESULTS: Zn and PTX increased proliferation inhibition in a dose- and time-dependent manner in prostate cancer cells, while Zn increased prostate cancer cell chemosensitivity to PTX. Combined Zn and PTX inhibited prostate cancer cell invasion and migration by downregulating the expression of TWIST1. Furthermore, knockdown of TWIST1 increased the sensitivity of prostate cancer cells to PTX. In addition, Zn and PTX reduced cell proliferation and induced apoptosis in prostate cancer cells. CONCLUSIONS: Our results demonstrated that Zn and PTX combined therapy inhibits EMT by reducing the expression of TWIST1, which reduces the invasion and migration of prostate cancer cells. SiTWIST1 increased the sensitivity of prostate cancer cells to PTX. In addition, with prolonged treatment, Zn and PTX inhibited proliferation and led to prostate cancer cell apoptosis. Therefore, Zn may be a potential adjuvant of PTX in treating prostate cancer and combined treatment may offer a promising therapeutic strategy for prostate cancer.


Assuntos
Apoptose/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Paclitaxel/farmacologia , Próstata , Neoplasias da Próstata , Zinco , Adjuvantes Farmacêuticos/metabolismo , Adjuvantes Farmacêuticos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Proteínas Nucleares/metabolismo , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteína 1 Relacionada a Twist/metabolismo , Zinco/metabolismo , Zinco/farmacologia
12.
Exp Cell Res ; 374(1): 249-258, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30528266

RESUMO

Many cell death regulators physically or functionally interact with metabolic enzymes. These interactions provide insights into mechanisms of anticancer treatments from the perspective of tumor cell metabolism and apoptosis. Recent studies have shown that zinc and p53 not only induce tumor cell apoptosis, but also regulate tumor cell metabolism. However, the underlying mechanism is complex and remains unclear, making further research imperative to provide clues for future cancer treatments. In this study, we found that hexokinase 2 (HK2), which has dual metabolic and apoptotic functions, is downstream of zinc and p53 in both prostate cancer patient tissue and prostate cancer cell lines. Notably, the mitochondrial location of HK2 is crucial for its function. We demonstrate that zinc and p53 disrupt mitochondrial binding of HK2 in prostate cancer cells by phosphorylating VDAC1, which is mediated by protein kinase B (Akt) inhibition and glycogen synthase kinase 3ß (GSK3ß) activation. In addition, we found that zinc combined with p53 significantly inhibited tumor growth in a prostate cancer cell xenograft model. Therefore, interference of the mitochondrial localization of HK2 by zinc and p53 may provide a new treatment approach for cancer.

13.
Genes Immun ; 20(2): 103-111, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29483615

RESUMO

Genetic variants near the tumor necrosis factor-α-induced protein 3 gene (TNFAIP3) at the chromosomal region 6q23 demonstrated significant associations with multiple autoimmune diseases. The signals of associations have been explained to the TNFAIP3 gene, the most likely causal gene. In this study, we employed CRISPR/cas9 genome-editing tool to generate cell lines with deletions including a candidate causal variant, rs6927172, at 140 kb upstream of the TNFAIP3 gene. Interestingly, we observed alterations of multiple genes including IL-20RA encoding a subunit of the receptor for interleukin 20. Using Electrophoretic mobility shift assay (EMSA), Western blotting, and chromatin conformation capture we characterized the molecular mechanism that the DNA element carrying the variant rs6927172 influences expression of IL-20RA and TNFAIP3 genes. Additionally, we developed a new use of the transcription activator-like effector (TALE) to study the role of the variant in regulating expressions of its target genes. In summary, we generated deletion knockouts that included the candidate causal variant rs6927172 in HEK293T cells provided new evidence and mechanism for IL-20RA gene as a risk factor for multiple autoimmune diseases.


Assuntos
Doenças Autoimunes/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Sistemas CRISPR-Cas , Células HEK293 , Humanos , Mutação , Receptores de Interleucina/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo
14.
Eur J Pharmacol ; 845: 56-64, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30582911

RESUMO

Cerebral ischemia-reperfusion injury is a thorny issue in the treatment of stroke. Energy depletion and oxidative stress are the core mechanisms underlying cerebral ischemia-reperfusion injury. Mitochondrial function is involved in energy production and oxidative stress. It has been reported that mitochondrial uncoupling protein 2 (UCP2) may be involved in the regulation of cerebral ischemia-reperfusion injury. We hypothesized that UCP2 can regulate cerebral ischemia-reperfusion injury by regulating energy supply and oxidative stress. To test this hypothesis, we used a middle cerebral artery occlusion model in male C57BL/6 mice with/without genipin--an UCP2-specific inhibitor. We measured the expression and/or activity of UCP2, SIRT3, the level of ATP, and antioxidant-related molecules in the cerebral cortex and the LDH in serum after ischemia-reperfusion, the level of apoptosis was reflected by the level of cleaved-caspase3 and tunel staining. The results showed an increase in the expression of UCP2, coinciding with an increase in the level of apoptosis, NAD+/NADH ratio, SIRT3 activity, LDH release and a decrease in the level of ATP and antioxidant-related molecules after 1 h of ischemia and 24 h of reperfusion. These findings suggest that UCP2 may regulate energy supply and oxidative stress in ischemia-reperfusion injury. Interestinly, above changes can be reserved by administration of genipin with the brain damage level going down. In conclusion, the UCP2-SIRT3 signaling pathway is involved in the regulation of cerebral ischemia-reperfusion injury as a bridge between energy metabolism and oxidative stress. Genipin protects against cerebral ischemia-reperfusion injury by inhibiting UCP2.


Assuntos
Iridoides/uso terapêutico , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Sirtuína 3/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Proteína Desacopladora 2/metabolismo , Animais , Apoptose , Metabolismo Energético , Iridoides/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de Sinais
15.
Oncol Rep ; 40(4): 2269-2277, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30106439

RESUMO

Paclitaxel­based chemotherapy is a promising approach for prostate cancer treatment. However, single­drug chemotherapy is associated with an increased risk of drug resistance. Therefore, novel combination chemotherapy regimens are a popular topic of research. Zinc participates in the regulation of apoptosis, for example in the form of Zn2+ and via zinc­dependent enzymes. Zinc can either induce or suppress apoptosis, and its effect depends primarily on its concentration. Previous research has demonstrated that physiological concentrations of zinc can directly induce apoptosis of PC­3 prostate cancer cells via the mitochondrial pathway. In prostate cancer tissues, zinc concentrations have been demonstrated to be reduced compared with non-cancerous tissues. Furthermore, the concentration of zinc has been demonstrated to decrease further with cancer progression. In the present study, it was investigated whether exposure of PC­3 cells to zinc improved their sensitivity to the chemotherapeutic agent, paclitaxel. MTT assays, cell clone formation assays, Hoechst staining and flow cytometry revealed that zinc enhanced PC­3­cell chemosensitivity to paclitaxel. Western blotting and reverse transcription­polymerase chain reaction were used to determine that the mitochondria­mediated apoptosis signaling pathway is involved with zinc/paclitaxel­induced cell death. The present study provides a foundation for the development of novel tumor combination therapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mitocôndrias/patologia , Paclitaxel/farmacologia , Neoplasias da Próstata/patologia , Zinco/farmacologia , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Células Tumorais Cultivadas
16.
Oncol Lett ; 16(3): 3509-3516, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30127955

RESUMO

Poor prognosis and chemotherapy tolerance are the main obstacles encountered in the treatment of cholangiocarcinoma. Chloroquine (CQ), an antimalarial agent, is able to induce sustained endoplasmic reticulum (ER) stress by functioning as an autophagy inhibitor. The present study indicated that CQ had the ability to induce apoptosis in QBC939 cholangiocarcinoma cells. Furthermore, using western blotting, Hoechst staining and flow cytometry, it was demonstrated that CQ induced the apoptosis of QBC939 cholangiocarcinoma cells. Analysis by a polymerase chain reaction (PCR) array and confirmation via quantitative PCR technology indicated that the expression levels of growth arrest and DNA damage 153 [C/EBP homologous protein (CHOP)], a key molecule involved in ER stress-induced apoptosis, and its downstream death receptors were increased following CQ stimulation. It was considered that the upregulation of CHOP may mediate CQ-induced extrinsic pathways and autophagy-dependent apoptosis; therefore, the role of autophagy in cholangiocarcinoma treatment was elucidated based on the data demonstrating that CQ regulates the ER-autophagy network in tumor cells. Furthermore, it was considered that CQ may become a novel and effective strategy for the treatment of cholangiocarcinoma.

17.
Int J Oncol ; 53(3): 1055-1068, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30015875

RESUMO

The poor prognosis and high mortality of patients with ovarian cancer result in part from their poor response to platinum-based chemotherapy. However, the precise mechanism behind cisplatin resistance is still not fully understood. In the present study, the authors explored the mechanism of resistance to cisplatin from the perspective of glucose metabolism in human ovarian cancer. The experiments using genetically matched ovarian cancer cell lines SKOV3 (cisplatin-sensitive) and SKOV3/DDP (cisplatin-resistant) in the present study provided some important findings. First, in comparison to SKOV3 cells, SKOV3/DDP cells exhibited decreased dependence on aerobic glycolysis and an increased demand for glucose. Secondly, the stable overexpression of Bcl­2 and ability to shift metabolism towards oxidative phosphorylation (OXPHOS) in SKOV3/DDP cells were associated with increased oxygen consumption. Furthermore, the metabolic characteristic of elevated OXPHOS primarily comprised most mitochondrial­derived reactive oxygen species (ROS) and, at least in part, contributed to the slight pro-oxidant state of SKOV3/DDP cells in turn. Thirdly, SKOV3/DDP cells reset the redox balance by overexpressing the key enzyme glucose 6-phosphate dehydrogenase (G6PD) of the pentose phosphate pathway to eliminate the cytotoxicity of highly elevated ROS. Furthermore, the inhibition of Bcl­2 reduced the OXPHOS and sensitivity of SKOV3/DDP cells to cisplatin in a selective manner. Furthermore, when combined with 2-deoxyglucose (2-DG), the anticancer effect of the Bcl­2 inhibitor ABT737 was greatly potentiated and hypoxia-inducible factor 1α (HIF­1α) appeared to be closely associated with Bcl­2 family members in the regulation of glucose metabolism. These results suggested that the special glucose metabolism in SKOV3/DDP cells might be selectively targeted by disrupting Bcl­2-dependent OXPHOS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos de Bifenilo/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glucose/metabolismo , Nitrofenóis/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Sulfonamidas/farmacologia , Antimetabólitos/farmacologia , Antimetabólitos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Desoxiglucose/farmacologia , Desoxiglucose/uso terapêutico , Sinergismo Farmacológico , Feminino , Glicólise/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nitrofenóis/uso terapêutico , Neoplasias Ovarianas/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/uso terapêutico
18.
Int J Oncol ; 53(1): 404-416, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29749474

RESUMO

The induction of lesions in nuclear and mitochondrial DNA by cisplatin is only a small component of its cytostatic/cytotoxic activity. The signaling pathway network in the nucleus and cytoplasm may contribute to chemotherapeutic resistance. Peroxisome proliferator-activated receptor-coactivator 1α (PGC1α)-mediated mitochondrial biogenesis regulates mitochondrial structural and the functional adaptive response against chemotherapeutic stress, and may be a therapeutic target. However, this regulatory network is complex and depends upon tumor types and environments, which require further investigation. Our previous study found that cisplatin-resistant ovarian epithelial carcinoma was more dependent on mitochondrial aerobic oxidation to support their growth, suggesting the association between mitochondrial function and chemotherapeutic resistance. In the present study, it was demonstrated that the expression of PGC1α and level of mitochondrial biogenesis were higher in cisplatin-resistant SKOV3/DDP cells compared with cisplatin-sensitive SKOV3 cells. Furthermore, SKOV3/DDP cells upregulated the expression of PGC1α and maintained mitochondrial structural and functional integrity through mitochondrial biogenesis under cisplatin stress. Inhibiting the expression of PGC1α using short hairpin RNA led to the downregulation of mitochondrial biogenesis and high levels of apoptosis in the SKOV3/DDP cells, and cisplatin resistance was reversed in the PGC1α-deficient SKOV3/DDP cells. Collectively, the present study provided evidence that cisplatin stimulated the expression of PGC1α and the upregulation of mitochondrial biogenesis through PGC1α, promoting cell viability and inhibiting apoptosis in response to cisplatin treatment, thus triggering cisplatin resistance in ovarian cancer cells.


Assuntos
Carcinoma/tratamento farmacológico , Cisplatino/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Apoptose/efeitos dos fármacos , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Biogênese de Organelas , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Transdução de Sinais/efeitos dos fármacos
19.
Cancer Cell Int ; 18: 58, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29686536

RESUMO

Background: Immunotoxins are typical therapeutic drugs that can target cancer cells. They exploit the affinity of specific monoclonal antibodies or ligands to cancer cells to deliver a conjugated protein toxin to target sites, thus, attacking the cancer cells. Methods: The immuno-RNase, Onc-V3, showed the stability of Onc-V3 in the blood stream. Flow cytometry showed that apoptosis occurred in the HO-8910PM cells when treated with Onc-V3. Under the confocal microscope, the green fluorescent, FITC-Onc-V3, were located in the cytoplasm, suggesting that Onc-V3 had a function in the cytoplasm of cancer cells. Moreover, after staining by DAPI, the blue fluorescent nuclei showed shrinkage and grainy. Wound healing assay showed that high concentrations of Onc-V3 inhibited cell migration and the transwell invasion assay showed that Onc-V3 could inhibit cell invasion to the basement membrane. Western blot results showed significantly decreased PARP, procaspase-9, and procaspase-3 in Onc-V3-induced apoptosis. Results: These results of the experiments in vitro had shown that the Onc-V3 could be delivered to the cancer cells accurately and it had strong cytotoxicity on high metastatic cancer cells. Conclusion: The specific toxicity of Onc-V3 on highly metastatic cancer cells can make it a promising anti-cancer drug by using V3 to target delivery of Onconase.

20.
Anat Rec (Hoboken) ; 301(8): 1390-1397, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29698579

RESUMO

Glioblastomas are the most frequently diagnosed and worst primary malignancy of the central nervous system, with very poor prognosis. The first-line antiglioma drug temozolomide shows decreasing therapeutic efficacy as treatment progresses. As the integrated stress response (ISR) may be a resistance factor and severe stress might transform the protective effect of the ISR into a damage effect, pharmacological regulation of ISR may be an effective way to sensitize glioma to temozolomide. The aim of the present study was to investigate the mechanisms of the ISR in regulating the therapeutic effect of temozolomide in the human glioblastoma multiforme cell line U87MG. Cultured U87MG cells were treated with temozolomide and PCR array was used to screen key factors in the response to treatment. Cells were co-treated with temozolomide and the eIF2α phosphatase inhibitor salubrinal, and cell apoptosis was measured. Combination treatment with temozolomide and salubrinal had a synergistic effect on cell viability. Salubrinal could upregulate the expression of ATF4, a key factor in the ISR, and enhance temozolomide-induced apoptosis. ATF4 transcriptionally regulated expression of the BH3-ONLY protein NOXA, thus inducing mitochondrial apoptosis. These findings suggest that ISR and ATF4 are involved in the death crosstalk between the endoplasmic reticulum and mitochondria and might be a potential target to enhance the therapeutic effect of temozolomide in patients with glioblastoma multiforme. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Glioblastoma , Mitocôndrias/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Temozolomida/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Apoptose/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Mitocôndrias/metabolismo , Estresse Fisiológico/fisiologia , Temozolomida/uso terapêutico
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