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1.
Cancer Cell Int ; 24(1): 38, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38238825

RESUMO

Drug resistance remains a challenge in ovarian cancer. In addition to aberrant activation of relevant signaling pathways, the adaptive stress response is emerging as a new spotlight of drug resistance in cancer cells. Stress granules (SGs) are one of the most important features of the adaptive stress response, and there is increasing evidence that SGs promote drug resistance in cancer cells. In the present study, we compared two types of ovarian cancer cells, A2780 and SKOV3, using the dual PI3K/mTOR inhibitor, PKI-402. We found that SGs were formed and SGs could intercept the signaling factor ATF5 and regulate the mitochondrial unfolded protein response (UPRmt) in A2780 cells. Therefore, exploring the network formed between SGs and membrane-bound organelles, such as mitochondria, which may provide a new insight into the mechanisms of antitumor drug functions.

3.
J Gastroenterol Hepatol ; 36(11): 3092-3101, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34089623

RESUMO

BACKGROUND AND AIM: The biological characterization of microbial environment in early gastric cancer (EGC), other than Helicobacter pylori, is limited. This study aimed to explore the microbial microenvironment in chronic gastritis (CG), fundic gland polyps (FGPs), low-grade intraepithelial neoplasia (LGIN), and EGC. METHODS: 16S-rRNA gene sequencing and bioinformatic analysis were performed on 63 individuals with 252 mucosal biopsies or endoscopic submucosal dissection margin samples from endoscopy. RESULTS: The microbiota in gastric LGIN functions analogously to EGC in terms of functional prediction. Neoplastic lesions showed a significant difference to CG or FGPs in beta diversity of the microbiota. Bacteria genera including Paracoccus, Blautia, Barnesiella, Lactobacillus, Thauera, Collinsella were significantly enriched in gastric neoplastic mucosa (LGIN and EGC) compared with non-neoplastic tissues (CG and FGPs). While Pseudomonas and Kingella were depleted in neoplastic tissues. FGPs showed a distinctive microbial network system that negatively interacted with Helicobacter. CONCLUSIONS: In terms of the mucosal microbial microenvironment, gastric LGIN and EGC showed no significant difference as early neoplastic lesions. We observed a coordinated microbial microenvironment that correlated negatively with Helicobacter.


Assuntos
Carcinoma in Situ , Mucosa Gástrica , Gastrite/microbiologia , Microbioma Gastrointestinal , Pólipos/microbiologia , Neoplasias Gástricas , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Biópsia , Carcinoma in Situ/microbiologia , Carcinoma in Situ/patologia , Doença Crônica , Endoscopia Gastrointestinal , Fundo Gástrico/microbiologia , Fundo Gástrico/patologia , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastrite/patologia , Microbioma Gastrointestinal/genética , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Humanos , Pólipos/patologia , RNA Ribossômico 16S/genética , Análise de Sequência de RNA , Gastropatias/microbiologia , Gastropatias/patologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , Microambiente Tumoral
4.
Onco Targets Ther ; 13: 9967-9976, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116582

RESUMO

PURPOSE: The chemoresistance and toxicity of traditional chemotherapeutic drugs have become obstacles to their antitumor effects in ovarian cancers. Therefore, it is particularly important to develop new anticancer drugs to increase target sensitivity and reduce the toxicity of chemotherapy drugs. As key organelles, the endoplasmic reticulum and mitochondria play important role in chemoresistance. Cells become resistant to drugs by maintaining the homeostasis of the endoplasmic reticulum and mitochondria. Chaetomugilin J, a metabolite isolated from Polygonatum sibiricum, belongs to the Chaetomium family and exhibits potent cytotoxicity. In this study, we aimed to explore the mechanistic link between apoptosis and endoplasmic reticulum stress, mitophagy and mitochondrial dysfunction induced by chaetomugilin J combined with cisplatin in the ovarian cancer cell line A2780. METHODS: Chaetomugilin J was identified by chemical methods. Cell viability was measured by an MTT assay. The apoptosis, mitochondrial membrane potential, and intracellular reactive oxygen species (ROS) were examined by flow cytometry. Mitochondrial ROS was measured by a fluorescence microscope with MitoSox staining. Further, the related proteins and overexpression of parkin were detected by Western blot. RESULTS: Chaetomugilin J combined with low-dose cisplatin decreased cell viability and increased apoptosis in A2780 cells. In addition, intracellular ROS and mitochondrial ROS were increased, while the mitochondrial membrane potential was reduced. The expressions of grp78 and chop were decreased after treatment by chaetomugilin J combined with low-dose cisplatin. Overexpression of parkin attenuated chaetomugilin J combined with cisplatin-induced apoptosis. CONCLUSION: Chaetomugilin J combined with cisplatin inhibited pink1/parkin mediated mitophagy increased mitochondrial dysfunction in the A2780 cells and enhanced apoptosis induced by cisplatin in the ovarian cancer cell line A2780. But this process was not related to endoplasmic reticulum apoptotic pathway.

5.
Biomed Pharmacother ; 129: 110397, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32585451

RESUMO

The phosphoinositide 3-kinase (PI3K) /AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently mutated in cancers, leading to increased cell proliferation, migration, and chemoresistance. Currently, a number of small molecule inhibitors of the PI3K/AKT/mTOR signaling pathway have been assessed in preclinical and clinical studies. It has been found that dual PI3K/mTOR inhibitors may inhibit cell proliferation and induce apoptosis in cancers, but the mechanism is still being explored. Therefore, determining the role of dual PI3K/mTOR inhibitors PKI-402 in cancer cells may facilitate overcoming chemoresistance. By referring to a gene database and screening gene sequences, we found that human ovarian cancer epithelial cell lines SKOV3 and A2780 had mutations of the PIK3CA gene, which might be relatively sensitive to dual-targeted PI3K/mTOR inhibitors. In this study, our data indicated that dual PI3K/mTOR inhibitor PKI-402 disrupted the balance of Bcl-2 family proteins by degrading the Mcl-1 protein through autophagy. Moreover, the autophagy receptor protein p62 bound to Mcl-1 through its ubiquitin-associated domain (UBA domain) to participate in the degradation of Mcl-1 through autophagy. This offers hope for the treatment of ovarian cancer patients with mutations of the PI3K/AKT/mTOR pathway.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Pirimidinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/enzimologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteólise , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
6.
BMC Complement Med Ther ; 20(1): 44, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046688

RESUMO

BACKGROUND: The effect of ginsenosides on the growth and apoptosis of human lens epithelial (HLE) B3 cells exposed to H2O2 was investigated. In addition, the effect of ginsenosides on gene expression in HLE-B3 cells was analyzed using microarray assays to determine its molecular mechanism. METHODS: HLE-B3 cells were treated with 1.75 M H2O2 in the presence or absence of 5, 10 or 20 µM ginsenosides. Cell viability and apoptosis were examined by MTT assays and flow cytometry, respectively, at 24 to 120 h after the treatment. Furthermore, HLE-B3 cells were treated with 20 µM ginsenosides for 8 days and total RNA was isolated and analyzed using the Affymetrix GeneChip Array. Principal component analysis was performed to visualize the microarray data. RESULTS: Addition of ginsenosides significantly alleviated the growth inhibitory effect of H2O2 on HLE-B3 cells and the percentage of viable cells was increased by more than 3 folds. Flow cytometric analysis showed that 6.16 ± 0.29% of H2O2-treated HLE-B3 cells were early apoptotic cells, and the percentage was reduced to 4.78 ± 0.16% (P < 0.05) in the presence of 20 µM ginsenosides. Principal component analysis revealed that ginsenoside caused extensive changes in gene expression in HLE-B3 cells. A total of 6219 genes showed significant differential expression in HLE-B3 cells treated with ginsenoside; among them, 2552 (41.0%) genes were significantly upregulated, whereas 3667 (59.0%) genes were significantly downregulated. FOXN2, APP and RAD23B were the top three upregulated genes while WSB1, PSME4 and DCAF7 were the top three downregulated genes in HLE-B3 cells treated with ginsenosides. CONCLUSION: Ginsenosides induce extensive changes in the expression of genes involved in multiple signaling pathways, including apoptotic signaling pathway and DNA damage response signaling pathway. Ginsenosides alleviate H2O2-induced suppression of the growth of HLB cells and inhibit H2O2-induced apoptosis of HLB cells.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/farmacologia , Cristalino/efeitos dos fármacos , Linhagem Celular , Citometria de Fluxo , Humanos , Cristalino/citologia , Panax notoginseng
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