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1.
Int J Mol Sci ; 23(22)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36430694

RESUMO

Hepatocellular carcinoma (HCC) is a major subtype of primary liver cancer with a high mortality rate. Pyroptosis and autophagy are crucial processes in the pathophysiology of HCC. Searching for efficient drugs targeting pyroptosis and autophagy with lower toxicity is useful for HCC treatment. Mallotucin D (MLD), a clerodane diterpenoid from Croton crassifolius, has not been previously reported for its anticancer effects in HCC. This study aims to evaluate the inhibitory effects of MLD in HCC and explore the underlying mechanism. We found that the cell proliferation, DNA synthesis, and colony formation of HepG2 cells and the angiogenesis of HUVECs were all greatly inhibited by MLD. MLD caused mitochondrial damage and decreased the TOM20 expression and mitochondrial membrane potential, inducing ROS overproduction. Moreover, MLD promoted the cytochrome C from mitochondria into cytoplasm, leading to cleavage of caspase-9 and caspase-3 inducing GSDMD-related pyroptosis. In addition, we revealed that MLD activated mitophagy by inhibiting the PI3K/AKT/mTOR pathway. Using the ROS-scavenging reagent NAC, the activation effects of MLD on pyroptosis- and autophagy-related pathways were all inhibited. In the HepG2 xenograft model, MLD effectively inhibited tumor growth without detectable toxicities in normal tissue. In conclusion, MLD could be developed as a candidate drug for HCC treatment by inducing mitophagy and pyroptosis via promoting mitochondrial-related ROS production.


Assuntos
Morte Celular Autofágica , Carcinoma Hepatocelular , Croton , Diterpenos Clerodânicos , Neoplasias Hepáticas , Humanos , Células Hep G2 , Piroptose , Carcinoma Hepatocelular/metabolismo , Diterpenos Clerodânicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Hepáticas/metabolismo , Proliferação de Células
2.
Cell Death Dis ; 13(11): 1007, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36443287

RESUMO

Ciclopirox (CPX), an antifungal drug, has recently been identified as a promising agent for cancer treatment. However, the effects and underlying mechanism of CPX as an antitumor agent of gastric cancer (GC) remain largely unknown. Here, we found that CPX dramatically suppresses GC xenograft growth in vitro via inhibiting proliferation and stimulating autophagic cell death rather than apoptosis. Moreover, CPX (20 mg/kg, intraperitoneally) substantially inhibits GC xenograft tumor growth in vivo. Mechanistically, CPX promotes growth arrest and autophagic cell death through suppressing the phosphorylation of signal transducers and activators of transcription 3 (STAT3) at tyrosine 705 (Tyr705) and serine 727 (Ser727) sites, respectively. Additionally, CPX induces STAT3 ubiquitination, which subsequently leads to a decrease in the p-STAT3 (Ser727) level. On the other hand, CPX represses the p-STAT3 (Tyr705) level via p-Src (Tyr416) inhibition. Collectively, our findings unmask a novel mechanism by which CPX regulates growth and autophagic cell death in GC cells via regulating the phosphorylation of STAT3 both at Tyr705 and Ser727 residues, and suggest that CPX may be a potential treatment for GC.


Assuntos
Morte Celular Autofágica , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Ciclopirox/farmacologia , Fosforilação , Serina , Tirosina , Fator de Transcrição STAT3
3.
Int J Mol Sci ; 23(19)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36232743

RESUMO

Glutamate-induced neural toxicity in autophagic neuron death is partially mediated by increased oxidative stress. Therefore, reducing oxidative stress in the brain is critical for treating or preventing neurodegenerative diseases. Selaginella tamariscina is a traditional medicinal plant for treating gastrointestinal bleeding, hematuria, leucorrhea, inflammation, chronic hepatitis, gout, and hyperuricemia. We investigate the inhibitory effects of Selaginella tamariscina ethanol extract (STE) on neurotoxicity and autophagic cell death in glutamate-exposed HT22 mouse hippocampal cells. STE significantly increased cell viability and mitochondrial membrane potential and decreased the expression of reactive oxygen species, lactate dehydrogenase release, and cell apoptosis in glutamate-exposed HT22 cells. In addition, while glutamate induced the excessive activation of mitophagy, STE attenuated glutamate-induced light chain (LC) 3 II and Beclin-1 expression and increased p62 expression. Furthermore, STE strongly enhanced the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) phosphorylation activation. STE strongly inhibited glutamate-induced autophagy by activating the PI3K/Akt/mTOR signaling pathway. In contrast, the addition of LY294002, a PI3K/Akt inhibitor, remarkably suppressed cell viability and p-Akt and p62 expression, while markedly increasing the expression of LC3 II and Beclin-1. Our findings indicate that autophagy inhibition by activating PI3K/Akt/mTOR phosphorylation levels could be responsible for the neuroprotective effects of STE on glutamate neuronal damage.


Assuntos
Morte Celular Autofágica , Fármacos Neuroprotetores , Selaginellaceae , Animais , Autofagia , Proteína Beclina-1/farmacologia , Etanol/farmacologia , Ácido Glutâmico/toxicidade , Lactato Desidrogenases/metabolismo , Mamíferos/metabolismo , Camundongos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Selaginellaceae/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
4.
Molecules ; 27(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36234769

RESUMO

Autophagy is the multistep mechanism for the elimination of damaged organelles and misfolded proteins. This mechanism is preceded and may induce other program cell deaths such as apoptosis. This study unraveled the potential pharmacological effect of 24MD in inducing the autophagy of lung cancer cells. Results showed that 24MD was concomitant with autophagy induction, indicating by autophagosome staining and the induction of ATG5, ATG7 and ubiquitinated protein, p62 expression after 12-h treatment. LC3-I was strongly conversed to LC3-II, and p62 was downregulated after 24-h treatment. The apoptosis-inducing activity was found after 48-h treatment as indicated by annexin V-FITC/propidium iodide staining and the activation of caspase-3. From a mechanistic perspective, 24-h treatment of 24MD at 60 µM substantially downregulated p-mTOR. Meanwhile, p-PI3K and p-Akt were also suppressed by 24MD at concentrations of 80 and 100 µM, respectively. We further confirmed m-TOR-mediated autophagic activity by comparing the effect of 24MD with rapamycin, a potent standard mTOR1 inhibitor through Western blot and immunofluorescence assays. Although 24MD could not suppress p-mTOR as much as rapamycin, the combination of rapamycin and 24MD could increase the mTOR suppressive activity and LC3 activation. Changing the substituent groups (R groups) from dimethylphenol to ethylphenol in EMD or changing methylazanedyl to cyclohexylazanedyl in 24CD could only induce apoptosis activity but not autophagic inducing activity. We identified 24MD as a novel compound targeting autophagic cell death by affecting mTOR-mediated autophagy.


Assuntos
Morte Celular Autofágica , Neoplasias Pulmonares , Apoptose , Autofagia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Propídio/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Ubiquitinadas/farmacologia , Proteínas Ubiquitinadas/uso terapêutico , Xilenos
5.
J Cell Mol Med ; 26(21): 5539-5550, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36251949

RESUMO

Larotrectinib (Lar) is a highly selective and potent small-molecule inhibitor used in patients with tropomyosin receptor kinase (TRK) fusion-positive cancers, including colon cancer. However, the underlying molecular mechanisms specifically in patients with colon cancer have not yet been explored. Our data showed that Lar significantly suppressed proliferation and migration of colon cancer cells. In addition, Lar suppressed the epithelial-mesenchymal transition (EMT) process, as evidenced by elevation in E-cadherin (E-cad), and downregulation of vimentin and matrix metalloproteinase (MMP) 2/9 expression. Furthermore, Lar was found to activate autophagic flux, in which Lar increased the ratio between LC3II/LC3I and decreased the expression of p62 in colon cancer cells. More importantly, Lar also increased AMPK phosphorylation and suppressed mTOR phosphorylation in colon cancer cells. However, when we silenced AMPK in colon cancer cells, Lar-induced accumulation of autolysomes as well as Lar-induced suppression of the EMT process were significantly diminished. An in vivo assay also confirmed that tumour volume and weight decreased in Lar-treated mice than in control mice. Taken together, this study suggests that Lar significantly suppresses colon cancer proliferation and migration by activating AMPK/mTOR-mediated autophagic cell death.


Assuntos
Morte Celular Autofágica , Neoplasias do Colo , Camundongos , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Autofagia , Neoplasias do Colo/tratamento farmacológico , Transição Epitelial-Mesenquimal , Linhagem Celular Tumoral , Proliferação de Células/fisiologia
6.
Biomed Res Int ; 2022: 6022981, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093402

RESUMO

Cisplatin resistance is one of the major obstacles in the treatment of nonsmall cell lung cancer (NSCLC). Kangai injection (KAI), a Chinese herbal medicine, has been used in tumors as adjuvant treatment, but its exact antitumor mechanism is still unclear. In this study, we first demonstrated that cisplatin-resistant A549/DDP cells showed a higher level of basal autophagy in response to cisplatin treatment with increasing autophagic protein expression levels of Beclin 1, p62, and LC3 compared to cisplatin-sensitive A549/DDP cells; then, we assessed the antitumor effect of KAI in cisplatin-resistant lung adenocarcinoma A549/DDP cells. Our results showed that KAI exhibited direct cytotoxic and chemosensitizing effects in A549/DDP cells. Combining KAI with cisplatin promoted A549/DDP cell apoptosis, which was confirmed by cell cycle arrest, condensed nuclear chromatin, annexin V fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining, and apoptosis-related protein expression. In addition, combining KAI with cisplatin induced autophagic cell death in A549/DDP cells with a high level of basal autophagy, as indicated by an increase in LC3 spot count, an accumulation of Beclin 1 and LC3 II, and reduced p62 protein expression. We also found that the apoptosis and autophagic cell death induced by cotreatment of KAI and cisplatin in A549/DDP cells were FOXO3a-dependent as indicated by decreased p-FOXO3a expression and increased FOXO3a nuclear localization, respectively. Furthermore, the FOXO3a gene knockdown assay further confirmed that KAI enhanced cisplatin cytotoxicity in A549/DDP cells with a high level of basal autophagy by inducing apoptosis and autophagic cell death in a FOXO3a-dependent manner. These findings suggest that the combination of KAI and cisplatin might support the potential clinical treatment as a novel strategy to overcome cisplatin resistance.


Assuntos
Adenocarcinoma de Pulmão , Morte Celular Autofágica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Apoptose , Autofagia , Proteína Beclina-1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/patologia
7.
Biomed Pharmacother ; 153: 113491, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076585

RESUMO

Cordyceps militaris is rich in adenosine derivatives, including 3'-deoxyadenosine, also known as cordycepin. It has been reported for antitumor effects, but its underlying molecular mechanism has yet to be elucidated. We investigated how adenosine derivatives exerted antitumor effects against ovarian cancer using human ovarian cancer cells and a xenograft mouse model. Treatment with adenosine derivatives effectively resulted in cell death of ovarian cancer cells through AMPK activation and subsequently mTOR-mediated autophagic induction. Intriguingly, the effect required membrane transport of adenosine derivatives via ENT1, rather than ADORA-mediated cellular signaling. Our data suggest that adenosine derivatives may be an effective therapeutic intervention in ovarian cancer through induction of ENT1-AMPK-mTOR-mediated autophagic cell death.


Assuntos
Adenosina , Morte Celular Autofágica , Cordyceps , Neoplasias Ovarianas , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Animais , Morte Celular Autofágica/efeitos dos fármacos , Carcinoma Epitelial do Ovário , Cordyceps/química , Desoxiadenosinas/farmacologia , Transportador Equilibrativo 1 de Nucleosídeo/efeitos dos fármacos , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo
8.
Acta Biomater ; 153: 518-528, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36152910

RESUMO

Doxorubicin (DOX) widely used in hepatocellular carcinoma (HCC) can induce serious side effects and drug resistance. Herein, we aimed to seek a strategy to improve the efficacy and reduce the side effects of DOX in HCC based on an autophagy inducer drug called isoginkgetin (ISO). The design of multifunctional nanocarriers based on hyaluronic acid-conjugated and manganese-doped mesoporous silica nanoparticles (HM) for the co-delivery of antitumor drugs against HCC provided an effective and promising antitumor strategy. Our results showed that HM@ISO@DOX could efficiently inhibit HCC cell proliferation through activating autophagy through AMPKa-ULK1 pathway. Moreover, intravenous injection of HM@ISO@DOX significantly suppressed HCC tumor progression in nude mouse HCC model. Collectively, our findings revealed an anti-HCC mechanism of HM@ISO@DOX through autophagy and provide an effective therapeutic strategy for HCC. STATEMENT OF SIGNIFICANCE: In our study, we constructed a co-delivery system by loading ISO and DOX in the mesoporous channels of manganese-doped mesoporous silica nanoparticles, which could be further conjugated with hyaluronic acid to obtain HM@ISO@DOX. The nanocarriers had been demonstrated to be biodegradable under the acidic and reducing tumor microenvironment, as well as to possess the tumor targeting capability via the conjugated hyaluronic acid. In addition, HM@ISO@DOX enhanced the therapeutic efficacy against human HCC tumor through the combinatorial therapies of chemotherapeutics, Mn2+-mediated chemodynamic therapeutics and autophagic cell death, which might be achieved through AMPK-ULK1 signaling. This work revealed that such a nanomedicine exhibited superior tumor accumulation and antitumor efficiency against HCC with extremely low systemic toxicity in an autophagy-boosted manner.


Assuntos
Morte Celular Autofágica , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Camundongos , Animais , Humanos , Carcinoma Hepatocelular/patologia , Ácido Hialurônico/farmacologia , Neoplasias Hepáticas/patologia , Manganês/farmacologia , Apoptose , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Nanopartículas/uso terapêutico , Dióxido de Silício/farmacologia , Linhagem Celular Tumoral , Microambiente Tumoral
9.
Med Oncol ; 39(12): 221, 2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36175804

RESUMO

Sorafenib (SOR) is currently the first line molecular targeting agent for advanced liver cancer therapy. Unfortunately, the insensitivity of liver cancer patients to SOR relatively limits its effectiveness. Huaier (HUA), a natural medicinal parasitic fungus found on the Sophora japonica Linn., has been widely employed as an adjuvant medication for numerous malignancies due to its potent anti-tumoral properties. This study aims to elucidate the enhancing therapeutic efficacy of HUA on SOR treatment in hepatocellular carcinoma (HCC) cells and mouse models. The CCK-8, clone formation, flow cytometry, immunofluorescence, transmission electron microscopy, western blot, bioinformatic analysis, and xenograft tumor assays were performed to evaluate the synergistic anti-hepatoma efficacy and mechanisms of HUA-SOR combination treatment on HCC cells. The results revealed combination treatment further inhibited proliferation, promoted apoptosis, enhanced autophagy of HCC cells, and suppressed the growth of transplanted tumors in mice, compared with either HUA or SOR treatment alone. For Hep3B and Huh7 cells, the optimal synergistic doses of HUA in combination with SOR were 8 mg/mL + 4 µM and 4 mg/mL + 2 µM, with combination index values of 0.646 and 0.588, respectively. Additionally, the underlying mechanisms might be related to biological processes that are mediated by mammalian target of rapamycin (mTOR). The combination treatment downregulated the protein expression levels of p-mTOR, p-p70S6K, p62, and upregulated the protein expression levels of Beclin-1 and LC3B-II. The mTOR activator MHY1485 attenuated the effect of HUA-SOR combination by inhibiting autophagy, suggesting HUA may potentiate the sensitivity of HCC cells to SOR by partially inducing mTOR-mediated autophagic cell death. These findings might provide a rationale experimental foundation for clinical applications of HUA with SOR.


Assuntos
Morte Celular Autofágica , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Proteína Beclina-1 , Carcinoma Hepatocelular/tratamento farmacológico , Misturas Complexas , Fungos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Mamíferos , Camundongos , Proteínas Quinases S6 Ribossômicas 70-kDa , Sincalida , Sirolimo , Sorafenibe/farmacologia , Serina-Treonina Quinases TOR , Trametes
10.
J Mol Cell Cardiol ; 173: 16-24, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36084743

RESUMO

Cardiomyocytes undergo various forms of cell death during heart disease such as myocardial infarction and heart failure. Understanding the mechanisms of cell death in cardiomyocytes is one of the most fundamental issues in the treatment of heart failure. Among the several kinds of cell death mechanisms, this review will focus on autophagy-related cardiomyocyte cell death. Although autophagy plays an essential role in mediating cellular quality control mechanisms for cell survival, dysregulation of autophagy can cause cell death, referred to as autophagy-dependent cell death or type II programmed cell death. The recent discovery of autosis as a modality of autophagy-dependent cell death with unique morphological and biochemical features has allowed us to broaden our understanding of the mechanistic role of autophagy in cell death. Here, we discuss autophagy-dependent cardiomyocyte cell death, including autosis, in pathophysiological conditions of the heart.


Assuntos
Morte Celular Autofágica , Cardiopatias , Insuficiência Cardíaca , Humanos , Autofagia/fisiologia , Miócitos Cardíacos/metabolismo , Cardiopatias/metabolismo , Insuficiência Cardíaca/metabolismo
11.
Biomed Pharmacother ; 153: 113443, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076558

RESUMO

16-hydroxycleroda-3,13-dien-15,16-olide (HCD) has antitumor activity reported in numerous types of cancers. However, the efficacy of HCD treatment in non-small-cell lung cancer (NSCLC) cells and doxorubicin-resistant (Dox-R)-NSCLC cells remains to be unraveled. The underlying anti-cancer mechanism of HCD on Dox-R and Dox-sensitive (Dox-S) of A549 cells was also investigated. Cytotoxicity of HCD against two cell lines (Dox-S and Dox-R) were determined via MTT assay, flow cytometry, and Western blot. A further examination of its anti-cancer efficacy was performed in A549-bearing xenograft mice via orthotopic intratrachea (IT) inoculation, which showed that HCD could arrest both Dox-S and Dox-R cells at G2/M phase without altering the sub-G1 cycle along with increasing of cleaved-PARP. HCD downregulated the mTOR/Akt/PI3K-p85 and PI3K-ClassIII/Beclin-1 signals and upregulated p62/LC3-I/II expressions to further confirm that the cell autophagy of NSCLC cells after being HCD-induced. Morphological observations of mouse lung sections illustrated that fewer cancer cells accumulated close to the trachea while less neoplastic activities were found in HCD orthotopic treated mice without liver, kidney, and spleen toxicity. Lastly, Dox, HCD, and target therapy medicines of EGFR and ALK were nicely docked with EGFR, ALK, and mTOR. Conclusively, HCD was demonstrated the chemotherapeutic potential regardless of Dox-R and Dox-S cells, suggesting natural autophagic inducer HCD provides a promising lead compound for new drug discovery and development of lung cancer therapies.


Assuntos
Morte Celular Autofágica , Carcinoma Pulmonar de Células não Pequenas , Diterpenos , Neoplasias Pulmonares , Animais , Apoptose , Autofagia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Receptores ErbB , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Fosfatidilinositol 3-Quinases , Receptores Proteína Tirosina Quinases , Serina-Treonina Quinases TOR/metabolismo
12.
J Reprod Immunol ; 153: 103681, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35964538

RESUMO

BACKGROUND: Hypercholesterolemia is defined as a high risk factor for causing female infertility by changing the cholesterol level in granulosa cells to impair the microenvironment of oocyte development and maturation. High blood levels of oxidized low-density lipoprotein (ox-LDL) undergoes an increase of autophagic granulosa cell death. Unfortunately, this underlying molecular mechanism remains largely elusive. We aim to uncover the role of circ-ubiquitin specific peptidase 36 (USP36) in autophagic granulosa cell death. METHODS: Exposure of ox-LDL on the ovarian granulosa cell-like human granulosa (KGN) cells line was established for simulating the situation of hypercholesterolemia in vitro. Levels of circUSP36 and ULK1 were detected using real-time polymerase chain reaction (RT-PCR). Cell viability and apoptosis were assessed using (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, respectively. Immunofluorescence staining of LC3 was performed to evaluate activity of autophagy. Western blot was employed to determine expression of apoptosis and autophagy-associated markers. RNA immunoprecipitation (RIP) and RNA pull-down assays were subjected to verify the circUSP36-PTBP1-NEDD4L regulatory axis. RESULTS: Treatment of ox-LDL induced aberrantly up-regulated circUSP36. Knockdown of circUSP36 alleviated cell apoptosis and excessive autophagy of granulosa cells triggered by ox-LDL. Mechanistically, reinforced expression of circUSP36 guided and facilitated PTBP1 binding to the coding region (CDS) of NEDD4L, resulting in NEDD4L mRNA decay. ULK1 was regulated by the circUSP36-PTBP1-NEDD4L axis in granulosa cells, thereby contributing to autophagic granulosa cell death. CONCLUSIONS: In summary, ox-LDL fostered autophagic granulosa cell death through circUSP36-mediated NEDD4L mRNA decay, thus elevating ULK1 expression.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Células da Granulosa , Ribonucleoproteínas Nucleares Heterogêneas , Ubiquitina-Proteína Ligases Nedd4 , Ubiquitina Tiolesterase , Apoptose/fisiologia , Morte Celular Autofágica/genética , Morte Celular Autofágica/fisiologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Brometos/metabolismo , Proliferação de Células , Células Cultivadas , Colesterol , DNA Nucleotidilexotransferase/metabolismo , Feminino , Células da Granulosa/metabolismo , Células da Granulosa/fisiologia , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/metabolismo , Hipercolesterolemia/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipoproteínas LDL/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Ubiquitina-Proteína Ligases Nedd4/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismo
13.
Cell Biol Int ; 46(12): 2095-2106, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36040726

RESUMO

Type 2 diabetes mellitus (T2DM) is a growing worldwide epidemic and is characterized by progressive pancreatic ß-cell dysfunction and insulin resistance. Tripartite motif protein 32 (TRIM32) belongs to the TRIM family protein and has been shown to be involve in insulin resistance in skeletal muscle and the liver. However, the effect of TRIM32 on pancreatic ß-cell dysfunction and its mechanism remains unknown. In the current study, we found that serum TRIM32 concentrations of T2DM in patients were significantly elevated compared to those in healthy controls, which indicated that TRIM32 might be used as a diagnostic biomarker in T2DM patients. In INS-1 cells, exposure to high glucose (HG) conditions caused a significant elevation in TRIM32 expression and TRIM32 was located in the nucleus. Overexpression of TRIM32 in INS-1 cells exacerbated the effects of HG-induced autophagy and impaired insulin secretion. In contrast, the silencing of TRIM32 produced the opposite effect. Furthermore, TRIM32 overexpression decreased the phosphorylation levels of Akt and mTOR under HG conditions. However, the activation of Akt/mTOR by MHY1485 reversed the effects of TRIM32 on HG-treated INS-1 cells. Collectively, the present results suggested that TRIM32 participates in the development of T2DM by modulating autophagic cell death and insulin secretion, which might occur through the Akt/mTOR pathway. Thus, TRIM32 might be a promising target in T2DM therapy.


Assuntos
Morte Celular Autofágica , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Proteínas com Motivo Tripartido/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Serina-Treonina Quinases TOR , Glucose/farmacologia , Glucose/metabolismo , Fatores de Transcrição/metabolismo
14.
Int J Mol Sci ; 23(16)2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-36012632

RESUMO

Colon cancer is a common malignant tumor of the digestive tract, and it is considered among the biggest killers. Scientific and reasonable treatments can effectively improve the survival rate of patients if performed in the early stages. Polyphyllin I (PPI), a pennogenyl saponin isolated from Paris polyphylla var. yunnanensis, has exhibited strong anti-cancer activities in previous studies. Here, we report that PPI exhibits a cytotoxic effect on colon cancer cells. PPI suppressed cell viability and induced autophagic cell death in SW480 cells after 12 and 24 h, with the IC50 values 4.9 ± 0.1 µmol/L and 3.5 ± 0.2 µmol/L, respectively. Furthermore, we found PPI induced time-concentration-dependent autophagy and apoptosis in SW480 cells. In addition, down-regulated AKT/mTOR activity was found in PPI-treated SW480 cells. Increased levels of ROS might link to autophagy and apoptosis because reducing the level of ROS by antioxidant N-acetylcysteine (NAC) treatment mitigated PPI-induced autophagy and apoptosis. Although we did not know the molecular mechanism of how PPI induced ROS production, this is the first study to show that PPI induces ROS production and down-regulates the AKT/mTOR pathway, which subsequently promotes the autophagic cell death and apoptosis of colon cancer cells. This present study reports PPI as a potential therapeutic agent for colon cancer and reveals its underlying mechanisms of action.


Assuntos
Morte Celular Autofágica , Neoplasias do Colo , Apoptose , Autofagia , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Diosgenina/análogos & derivados , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo
15.
Molecules ; 27(16)2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-36014455

RESUMO

Cadmium (Cd), a harmful heavy metal, can lead to various pulmonary diseases, including chronic obstructive pulmonary disease (COPD), by inducing cytotoxicity and disturbing redox homeostasis. The aim of the present study was to investigate Cd-mediated cytotoxicity using human lung fibroblasts and the therapeutic potential of 3,3'-diindolylmethane (DIM). Cadmium significantly reduced the cell viability of human embryonic lung (HEL299) cells accompanied by enhanced oxidative stress as evidenced by the increased expression of autophagy-related proteins such as LC3B and p62. However, treatment with DIM significantly suppressed autophagic cell death in Cd-induced HEL299 fibroblasts. In addition, DIM induced antioxidant enzyme activity and decreased intracellular reactive oxygen species (ROS) levels in Cd-damaged HEL299 cells. This study suggests that DIM effectively suppressed Cd-induced lung fibroblast cell death through the upregulation of antioxidant systems and represents a potential agent for the prevention of various diseases related to Cd exposure.


Assuntos
Morte Celular Autofágica , Cádmio , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose , Autofagia , Cádmio/toxicidade , Fibroblastos/metabolismo , Humanos , Indóis , Pulmão/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
16.
Cell Death Dis ; 13(8): 711, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35974000

RESUMO

Lung cancer remains one of the most common malignancies and the leading cause of cancer-related death worldwide. Forkhead box protein A1 (FOXA1) is a pioneer factor amplified in lung adenocarcinoma (LUAD). However, its role in LUAD remains elusive. In this study, we found that expression of FOXA1 enhanced LUAD cell survival in nutrients deprived conditions through inhibiting autophagic cell death (ACD). FOXA1 bound to the imprinting control region of insulin-like growth factor 2 (IGF2) and interacted with DNA methyltransferase 1 (DNMT1), leading to initiation of DNMT1-mediated loss of imprinting (LOI) of IGF2 and autocrine of IGF2. Blockage of IGF2 and its downstream insulin-like growth factor 1 receptor (IGF1R) abolished the protective effect of FOXA1 on LUAD cells in nutrients deprived conditions. Furthermore, FOXA1 suppressed the expression of the lysosomal enzyme glucocerebrosidase 1 (GBA1), a positive mediator of ACD, through ubiquitination of GBA1 enhanced by IGF2. Notably, FOXA1 expression in A549 cells reduced the efficacy of the anti-angiogenic drug nintedanib to inhibit xenograft tumor growth, whereas a combination of nintedanib with IGF1R inhibitor linsitinib or mTORC1 inhibitor rapamycin enhanced tumor control. Clinically, high expression level of FOXA1 protein was associated with unfavorable prognosis in LUAD patients of advanced stage who received bevacizumab treatment. Our findings uncovered a previously unrecognized role of FOXA1 in mediating loss of imprinting of IGF2, which confer LUAD cells enhanced survival ability against nutrients deprivation through suppressing autophagic cell death.


Assuntos
Adenocarcinoma de Pulmão , Morte Celular Autofágica , Fator 3-alfa Nuclear de Hepatócito , Fator de Crescimento Insulin-Like II , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Impressão Genômica , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Fator de Crescimento Insulin-Like II/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Nutrientes
17.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 30(4): 1011-1017, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-35981355

RESUMO

OBJECTIVE: To investigate the potential value and its mechanism of dihydroartemisinin (DHA) in the treatment of acute myeloid leukemia (AML). METHODS: The effect of DHA on the viability of AML cells was detected by CCK-8 assay. The effect of DHA on intracellular oxidation-reduction state was detected by fluorescence probe staining and flow cytometry. Western blot, adenovirus transfection, and laser confocal analysis were used to analyze the effect of DHA on autophagy. The small molecule inhibitors were used to further elucidate the possible mechanism of DHA-induced AML cell death. RESULTS: DHA could inhibit the viability of HL-60 and Kasumi-1 cell lines, and significantly increase the level of intracellular oxidative stress. When treated with 10 µmol/L DHA, reactive oxygen species (ROS) in HL-60 cells and Kasumi-1 cells was increased to 2.6 times and 2.0 times, respectively. In addition, the expression of autophagy-related proteins were up-regulated in DHA-treated AML cells, together with the increase of intracellular autophagy flux and activation of autophagy. Furthermore, autophagy inhibitors reduced DHA-induced cell death, and inhibited the level of oxidative stress by scavenging intracellular free radicals, thus inhibiting autophagy and restoring cell viability. CONCLUSION: DHA can activate autophagic cell death of AML by inducing oxidative stress.


Assuntos
Artemisininas , Morte Celular Autofágica , Leucemia Mieloide Aguda , Apoptose , Artemisininas/farmacologia , Autofagia , Humanos , Estresse Oxidativo
18.
Planta Med ; 88(13): 1116-1122, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35853472

RESUMO

The incidence of skin cancer has been increasing over the past decades, and melanoma is considered highly malignant because of its high rate of metastasis. Plant-derived berberine, an isoquinoline quaternary alkaloid, has been reported to possess multiple pharmacological effects against various types of cancer cells. Therefore, we treated melanoma B16F10 cells with berberine to induce cell death and understand the cell death mechanisms. The berberine-treated cells showed decreased cell viability, according to berberine concentration. However, western blot analysis of apoptosis-related marker proteins showed that the expression of Bcl-2, an apoptosis inhibitory protein, and the Bcl-2/Bax ratio were increased. Therefore, by adding 3-methyladenine to the berberine-treated cells, we investigated whether the reduced cell viability was due to autophagic cell death. The results showed that 3-methyladenine restored the cell viability decreased by berberine, suggesting autophagy. To clarify autophagic cell death, we performed transmission electron microscopy analysis, which revealed the presence of autophagosomes and autolysosomes in the cells after treatment with berberine. Next, by analyzing the expression of autophagy-related proteins, we found an increase in the levels of light chain 3A-II and Atg12-Atg5 complex in the berberine-treated cells. We then assessed the involvement of the Akt/mTOR signaling pathway and found that berberine inhibited the expression of phosphorylated Akt and mTOR. Our data demonstrated that berberine induces autophagic cell death by inactivating the Akt/mTOR signaling pathway in melanoma cells and that berberine can be used as a possible target for the development of anti-melanoma drugs.


Assuntos
Morte Celular Autofágica , Berberina , Berberina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína X Associada a bcl-2 , Apoptose , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/metabolismo , Transdução de Sinais , Autofagia , Proteínas Reguladoras de Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Relacionadas à Autofagia/farmacologia , Isoquinolinas/farmacologia
19.
Cell Rep ; 40(3): 111077, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858554

RESUMO

Redox-active metal ions are pivotal for rapid metabolism, proliferation, and aggression across cancer types, and this presents metal chelation as an attractive cancer cell-targeting strategy. Here, we identify a metal chelator, KS10076, as a potent anti-cancer drug candidate. A metal-bound KS10076 complex with redox potential for generating hydrogen peroxide and superoxide anions induces intracellular reactive oxygen species (ROS). The elevation of ROS by KS10076 promotes the destabilization of signal transducer and activator of transcription 3, removes aldehyde dehydrogenase isoform 1-positive cancer stem cells, and subsequently induces autophagic cell death. Bioinformatic analysis of KS10076 susceptibility in pan-cancer cells shows that KS10076 potentially targets cancer cells with increased mitochondrial function. Furthermore, patient-derived organoid models demonstrate that KS10076 efficiently represses cancer cells with active KRAS, and fluorouracil resistance, which suggests clinical advantages.


Assuntos
Morte Celular Autofágica , Fator de Transcrição STAT3 , Família Aldeído Desidrogenase 1 , Apoptose , Linhagem Celular Tumoral , Quelantes , Humanos , Células-Tronco Neoplásicas/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Superóxidos/metabolismo
20.
Cell Death Dis ; 13(7): 603, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35831271

RESUMO

Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC38 or B16-F10 preclinical syngeneic tumor models. These results elucidate the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.


Assuntos
Antineoplásicos , Morte Celular Autofágica , Neoplasias Colorretais , Animais , Antineoplásicos/farmacologia , Autofagia , Benzimidazóis , Colesterol/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Serina-Treonina Quinases TOR/metabolismo
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