CCT196969 effectively inhibits growth and survival of melanoma brain metastasis cells.
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ABSTRACT:
ORGANISM(S): Homo sapiens (human)
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PROVIDER: S-BIAD468 | bioimages |
REPOSITORIES: bioimages
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Project description:Androgen receptor (AR) and its constitutively active variants (AR-Vs) have been extensively implicated in the progression and recurrence of prostate cancer, making them attractive targets in the treatment of this disease. Whether and how neddylation modification regulates AR, and the therapeutic implications of this potential regulation, are relatively unexplored areas of investigation. Here we report that neddylation inactivation by the pharmacological inhibitor MLN4924 or Lenti-shRNA-based genetic knockdown of neddylation activating enzyme (NAE) selectively suppressed growth and survival of prostate cancer cells with minor, if any, effect on normal prostate epithelial cells. MLN4924 also significantly suppressed the invasive capacity of prostate cancer cells. Furthermore, compared to monotherapy, the combination of MLN4924 with AR antagonist or castration significantly enhanced growth suppression of prostate cancer cells in vitro, and tumor growth in an in vivo xenograft model. Mechanistically, MLN4924 repressed the transcription of AR/AR-V7 and its downstream targets, and blocked MMP2 and MMP9 expression. Taken together, our study reveals that the neddylation pathway positively regulates AR/AR-V7 transcription, and that the neddylation inhibitor MLN4924 has therapeutic potential for the treatment of aggressive prostate cancers.
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Project description:The hepatocyte growth factor (HGF)/MNNG HOS transforming gene (MET) pathway regulates cell growth, survival, and migration. MET is mutated or amplified in several malignancies. In myeloma, MET is not mutated, but patients have high plasma concentrations of HGF, high levels of MET expression, and gene copy number, which are associated with poor prognosis and advanced disease. Our previous studies demonstrated that MET is critical for myeloma cell survival and its knockdown induces apoptosis. In our current study, we tested tivantinib (ARQ 197), a small-molecule pharmacological MET inhibitor. At clinically achievable concentrations, tivantinib induced apoptosis by >50% in all 12 human myeloma cell lines tested. This biologic response was associated with down-regulation of MET signaling and inhibition of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, which are downstream of the HGF/MET axis. Tivantinib was equally effective in inducing apoptosis in myeloma cell lines resistant to standard chemotherapy (melphalan, dexamethasone, bortezomib, and lenalidomide) as well as in cells that were co-cultured with a protective bone marrow microenvironment or with exogenous cytokines. Tivantinib induced apoptosis in CD138+ plasma cells from patients and demonstrated efficacy in a myeloma xenograft mouse model. On the basis of these data, we initiated a clinical trial for relapsed/refractory multiple myeloma (MM). In conclusion, MET inhibitors may be an attractive target-based strategy for the treatment of MM.
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Project description:Electrochemical reduced water (ERW) has been proposed to have beneficial effects on human health due to its rich content of H2 and the presence of platinum nanoparticles with antioxidant effects. Many studies have demonstrated that ERW scavenging properties are able to reduce the damage caused by oxidative stress in different experimental models. Although few in vivo studies have been reported, it has been demonstrated that ERW may display anticancer effects by induction of tumor cells apoptosis and reduction of both angiogenesis and inflammation. In this study, we show that ERW treatment of MCF-7, MDA-MB-453, and mouse (TUBO) breast cancer cells inhibited cell survival in a time-dependent fashion. ERW decreased ErbB2/neu expression and impaired pERK1/ERK2 and AKT phosphorylation in breast cancer cells. In addition, ERW treatment induced apoptosis of breast cancer cell lines independently of the status of p53 and ER and PR receptors. Our in vivo results showed that ERW treatment of transgenic BALB-neuT mice delayed the development of mammary tumors compared to the control. In addition, ERW induced a significant prolongation of tumor-free survival and a reduction in tumor multiplicity. Overall, these results suggest a potential beneficial role of ERW in inhibiting cancer cells growth.
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Project description:Brain glioma is a common gynecological tumor. MicroRNA (miRNA) plays a very important role in the pathogenesis and development of tumors. It was found that glycolysis played important regulatory roles in tumor growth. The present study aims to investigate the expression pattern of miR-21-5p in brain glioma cells. We examined miR-21-5p and PFKFB2 levels in brain glioma cells via qRT-PCR. Then we performed CCK-8 and Transwell migration assays and determined glucose uptake and lactose production to unveil the properties of miR-21-5p in invasion, cell viability, along with glycolysis in brain glioma cells. Luciferase activity assay was implemented to elucidate if PFKFB2 was a miR-21-5p target gene. Western blotting and qRT-PCR were executed to further validate that miR-21-5p targeted PFKFB2. We repeated these functional assays to observe whether miR-21-5p could impede the function of PFKFB2. qRT-PCR signified that miR-21-5p was elevated in brain glioma tissues in contrast to matching adjacent normal tissues. Functional assays disclosed that elevation of miR-21-5p promoted cell viability, invasion, together with glycolysis. Luciferase assay indicated that PFKFB2 was a miR-21-5p target gene. Moreover, miR-21-inhibit could hinder cell viability, invasion, and glycolysis triggered by overexpression of PFKFB2 in brain glioma cells. miR-21-5p level is elevated in brain glioma and can impede brain glioma cell growth via regulating the glycolysis mediated by PFKFB2, thus is a potential target of treating brain glioma.
| S-EPMC10590297 | biostudies-literature
Project description:Although aberrant Notch activation contributes to leukemogenesis in T cells, its role in acute myelogenous leukemia (AML) remains unclear. Here, we report that human AML samples have robust expression of Notch receptors; however, Notch receptor activation and expression of downstream Notch targets are remarkably low, suggesting that Notch is present but not constitutively activated in human AML. The functional role of these Notch receptors in AML is not known. Induced activation through any of the Notch receptors (Notch1-4), or through the Notch target Hairy/Enhancer of Split 1 (HES1), consistently leads to AML growth arrest and caspase-dependent apoptosis, which are associated with B cell lymphoma 2 (BCL2) loss and enhanced p53/p21 expression. These effects were dependent on the HES1 repressor domain and were rescued through reexpression of BCL2. Importantly, activated Notch1, Notch2, and HES1 all led to inhibited AML growth in vivo, and Notch inhibition via dnMAML enhanced proliferation in vivo, thus revealing the physiological inhibition of AML growth in vivo in response to Notch signaling. As a novel therapeutic approach, we used a Notch agonist peptide that led to significant apoptosis in AML patient samples. In conclusion, we report consistent Notch-mediated growth arrest and apoptosis in human AML, and propose the development of Notch agonists as a potential therapeutic approach in AML.
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Project description:BackgroundProtein disulfide isomerase A3 (PDIA3, also named GRP58, ER-60, ERp57) is conserved across species and mediates protein folding in the endoplasmic reticulum. PDIA3 is, reportedly, a chaperone for STAT3. However, the role of PDIA3 in regulating mitochondrial bioenergetics and STAT3 phosphorylation at serine 727 (S727) has not been described.MethodsMitochondrial respiration was compared in immortalized human cerebral microvascular cells (CMEC) wild type or null for PDIA3 and in whole organism C. Elegans WT or null for pdi-3 (worm homologue). Mitochondrial morphology and cell signaling pathways in PDIA3-/- and WT cells were assessed. PDIA3-/- cells were subjected to oxygen-glucose deprivation (OGD) to determine the effects of PDIA3 on cell survival after injury.ResultsWe show that PDIA3 gene deletion using CRISPR-Cas9 in cultured CMECs leads to an increase in mitochondrial bioenergetic function. In C. elegans, gene deletion or RNAi knockdown of pdi-3 also increased respiratory rates, confirming a conserved role for this gene in regulating mitochondrial bioenergetics. The PDIA3-/- bioenergetic phenotype was reversed by overexpression of WT PDIA3 in cultured PDIA3-/- CMECs. PDIA3-/- and siRNA knockdown caused an increase in phosphorylation of the S727 residue of STAT3, which is known to promote mitochondrial bioenergetic function. Increased respiration in PDIA3-/- CMECs was reversed by a STAT3 inhibitor. In PDIA3-/- CMECs, mitochondrial membrane potential and reactive oxygen species production, but not mitochondrial mass, was increased, suggesting an increased mitochondrial bioenergetic capacity. Finally, PDIA3-/- CMECs were more resistant to oxygen-glucose deprivation, while STAT3 inhibition reduced the protective effect.ConclusionsWe have discovered a novel role for PDIA3 in suppressing mitochondrial bioenergetic function by inhibiting STAT3 S727 phosphorylation.
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Project description:Dpep is a cell-penetrating peptide targeting transcription factors ATF5, CEBPB and CEBPD that selectively promotes apoptotic death of multiple tumor cell types in vitro and in vivo. To better understand its mechanism of action, we compared transcriptomes of 6 cancer cell lines of varying origins before and after Dpep exposure. This revealed a context-dependent pattern of regulated genes that was unique to each line, but that exhibited a number of shared elements with other lines. This included upregulation of pro-apoptotic genes and tumor suppressors as well as enrichment of genes associated with responses to hypoxia and interferons. Downregulated transcripts included oncogenes and dependency genes and enriched genes associated with different phases of the cell cycle as well as with DNA repair. In each case, such changes have the potential to lie upstream of apoptotic cell death. We also detected regulation of unique as well as shared sets of transcription factors in each line, suggesting that Dpep may initiate a cascade of transcriptional responses that culminate in cancer cell death. Such death thus appears to reflect context-dependent, yet shared disruption of multiple cellular pathways as well as of individual survival-relevant genes.
2023-10-10 | GSE244579 | GEO
Project description:Synthetic triterpenoids are potent anticancer agents, but their therapeutic efficacy or mechanism of action for prostate cancer has not been investigated. The goal of this study was to determine the antitumor activity and the mechanism of action of methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane-derived synthetic triterpenoid for human prostate cancer cells.The antitumor activity of CDDO-Me for hormone-refractory PC-3 (AR(-)) and C4-2 (AR(+)) prostate cancer cell lines was determined by effects on cell growth and induction of apoptosis, identification of molecular targets, and therapeutic efficacy in vivo in PC-3 xenograft model.CDDO-Me inhibited the growth and induced apoptosis in PC-3 and C4-2 cells at extremely low concentrations. The antitumor activity of CDDO-Me was associated with the inhibition of p-Akt, mammalian target of rapamycin (mTOR), and nuclear factor kappa B (NF-kappaB) signaling proteins and their downstream targets such as p-Bad and p-Foxo3a (Akt); p-S6K1, p-eIF-4E and p-4E-BP1 (mTOR); and COX-2, VEGF and cyclin D1(NF-kappaB). Silencing of Akt sensitized the PC-3 cells to CDDO-Me, whereas overexpression of Akt induced resistance to CDDO-Me. Targeted silencing of Akt showed that Akt does not regulate mTOR activation in PC-3 cells, but targeted silencing of mTOR sensitized PC-3 cells to CDDO-Me mediated growth inhibition. Further, treatment with CDDO-Me inhibited the growth of PC-3 xenografts in nude mice.This study demonstrated potent antitumor activity of CDDO-Me against prostate cancer cells both in vitro and in vivo. Data also identified Akt and mTOR as molecular targets of CDDO-Me in prostate cancer cells.
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Project description:We have previously shown that L-methionine inhibits proliferation of breast, prostate, and colon cancer cells. This study extends these findings to BXPC-3 (mutated p53) and HPAC (wild-type p53) pancreatic cancer cells and explores the reversibility of these effects. Cells were exposed to L-methionine (5 mg/ml) for 7 days or for 3 days, followed by 4 days of culture without L-methionine (recovery). Cell proliferation, apoptosis, and cell cycle effects were assessed by flow cytometry after staining for Ki-67 or annexin V/propidium iodide. Cell proliferation was reduced by 31-35% after 7 days of methionine exposure; the effect persisted in BXPC-3 and HPAC cells after 4 days of recovery. Methionine increased apoptosis by 40-75% in HPAC cells, but not in BXPC-3 cells. Continuous exposure to methionine caused accumulation of BXPC-3 cells in the S phase and HPAC cells in both the G0/G1 and S phases; however, after 4 days of recovery, these effects disappeared. In conclusion, L-methionine inhibits proliferation and interferes with the cell cycle of BXPC-3 and HPAC pancreatic cancer cells; the effects on apoptosis remarkably persisted after methionine withdrawal. Apoptosis was induced only in BXPC-3 cells. Some of the differences in the effects of methionine between cell lines may be related to disparate p53 status. These findings warrant further studies on the potential therapeutic benefit of L-methionine against pancreatic cancer.
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Project description:Medulloblastoma is the most common malignant brain tumor in children, and a substantial number of patients die as a result of tumor progression. Overexpression of CDK6 is present in approximately one-third of medulloblastomas and is an independent poor prognostic marker for this disease. MicroRNA (miR)-124 inhibits expression of CDK6 and prevents proliferation of glioblastoma and medulloblastoma cells in vitro. We examined the effects of miR-124 overexpression on medulloblastoma cells both in vitro and in vivo and compared cell lines that have low and high CDK6 expression. MiR-124 overexpression inhibits the proliferation of medulloblastoma cells, and this effect is mediated mostly through the action of miR-124 upon CDK6. We further show that induced expression of miR-124 potently inhibits growth of medulloblastoma xenograft tumors in rodents. Further testing of miR-124 will help define the ultimate therapeutic potential of preclinical models of medulloblastoma in conjunction with various delivery strategies for treatment.
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