Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been reported that microRNA-142 (miR-142) is a tumor suppressor gene. The present study primarily investigated whether the overexpression of miR-142 was able to inhibit the proliferation, apoptosis and expression of apoptosis-associated proteins in osteosarcoma (OS) cells. Different concentrations of miR-142 were transfected into the OS MG-63 cell line using Lipofectamine 2000. The cell lines were divided into three groups: Normal group (non-transfected group), miR-142 transfected group, and negative group, which were transfected with random miR-142 fragment. The proliferation of cells was detected by MTT assay. The expression of miR-142 was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). DAPI staining was performed to investigate the influence of miR-142 on the morphology of MG-63c ells. The apoptotic cell percentages were determined by flow cytometry with Annexin V-fluorescein isothiocyanate/propidium iodide double staining. Expression of tumor suppressors, phosphatase and tensin homolog (PTEN) and Retinoblastoma-associated protein (Rb), and apoptosis-associated proteins were evaluated by western blotting. RT-qPCR indicated a higher expression of miR-142 in the transfected group (miR-142 was transfected into the MG-63 cell line) compared with that in the normal (non-transfected group) and negative control groups. The proliferation of miR-142 transfected cells was significantly lower compared with that in the normal and negative groups. Furthermore, an increased apoptosis rate accompanied by a statistically significant upregulation of PTEN, Rb phosphorylation, cleaved caspase-3 and cytochrome c protein levels were detected in the transfected group, indicating an internal apoptosis pathway was involved in this process. Furthermore, no significant changes were identified between the normal and negative groups (P>0.05). The present study demonstrated that miR-142 overexpression by liposomal transfection resulted in an inhibitory effect on MG-63 cell proliferation. The underlying mechanisms may relate to the upregulation of tumor suppressor and activation of caspase signaling pathway, which may provide a novel horizon in short nucleotide drugs on the management of OS.
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PMID:miR-142 suppresses proliferation and induces apoptosis of osteosarcoma cells by upregulating Rb. 2996 39

Chemoresistance is a major obstacle in treating cancer, including osteosarcoma. LncRNA ANRIL (ANRIL) is involved in the growth and metastasis of osteosarcoma cells, however, its role in chemoresistance remains unclear. In this study, ANRIL shRNA was used to knock down its endogenous expression in U2-OS and Saos-2 osteosarcoma cell lines. Our data showed that ANRIL-silenced cells were more sensitive to cisplatin: apoptotic ratio was increased and cleaved caspase-3 level was upregulated. Furthermore, the expression level of miR-125a-5p, a microRNA that can bind to ANRIL, was elevated in ANRIL-silenced cells. MiR-125a-5p inhibitor attenuated ANRIL knockdown-induced chemosensitivity to cisplatin. In addition, ANRIL knockdown resulted in a reduction in STAT3, a target of miR-125a-5p, in osteosarcoma cells. Forced overexpression of STAT3 weakened the chemosensitivity of ANRIL-silenced cells to cisplatin. In conclusion, our study demonstrates that ANRIL knockdown sensitizes osteosarcoma cells to cisplatin-induced cytotoxicity, suggesting ANRIL as a therapeutic target for osteosarcoma chemotherapy.
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PMID:Effect of lncRNA ANRIL knockdown on proliferation and cisplatin chemoresistance of osteosarcoma cells in vitro. 3077 16

PDZ domain containing 2 (PDZD2) is a multi-PDZ domain protein that promotes the proliferation of insulinoma cells, and is upregulated during prostate tumorigenesis. However, the function of PDZD2 in other cancers, including osteosarcoma (OS), remains unclear. Dysregulation of microRNAs (miRNAs) contributes to tumor initiation, proliferation and metastasis, via the regulation of their target genes. The present study investigated the functions of miR-363 and PDZD2 in MG-63 OS cells. The results revealed that MG-63 cells contained low levels of miR-363, and that overexpression of miR-363 in MG-63 cells significantly inhibited the vitality, proliferation, and colony formation ability of the cells, but promoted their apoptosis and G1/S arrest by regulating proliferating cell nuclear antigen (PCNA) and caspase-3 expression. Additionally, miR-363 impaired the migration and invasion of MG-63 cells by regulating the epithelial-mesenchymal transition (EMT) phenotype. Notably, a bioinformatics analysis and luciferase reporter assay indicated that PDZD2 was a direct target of miR-363. miR-363 overexpression reduced PDZD2 protein levels and knockdown of PDZD2 suppressed the colony formation, migration and invasion of MG-63 cells, but promoted their apoptosis by regulating expression of PCNA, caspase-3, and the EMT phenotype. In vivo studies further confirmed that miR-363 functioned as tumor suppressor, by inhibiting tumor growth, promoting cell apoptosis, and reducing PDZD2 and PCNA levels and the prevalence of the EMT phenotype in tumor tissues. The present data demonstrated that downregulation of the tumor suppressor miR-363 may be involved in the development of osteosarcoma via regulation of PDZD2.
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PMID:miR-363 acts as a tumor suppressor in osteosarcoma cells by inhibiting PDZD2. 3089 77

Novel therapeutic strategies are still urgently expected for leukemia despite undisputed success of various targeted therapeutics. The antileukemia activity of Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on human leukemia cells was investigated. Atorvastatin inhibited K562 and HL60 cell proliferation, induced G2/M cell cycle arrest in K562 cells by down-regulating cyclinB1 and cdc2, but G0/G1 arrest in HL60 cells by up-regulating p27 and down-regulating cyclinD1 and p-pRb. Atorvastatin also induced apoptosis in both cell lines, in which the reactive oxygen species (ROS)-related mitochondrial apoptotic signaling might be involved, with increase of ROS and Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP), release of cytochrome C into cytosol, and activation of Bax/Caspase-9/Caspase-3/PARP pathway. Inhibition of YAP nuclear localization and activation by Atorvastatin was reversed by the addition of mevalonate, GGPP, or FPP. Further, the effects on cell cycle arrest- and apoptosis- related proteins by Atorvastatin were alleviated by addition of mevalonate, suggesting the antileukemia effect of Atorvastatin might be through mevalonate-YAP axis in K562 and HL60 cells. Our results suggest that Atorvastatin might be used for leukemia therapy while evidence of clinical efficacy is required.
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PMID:Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 Cells. 3164 88

Enhancer of zeste homolog 2 (EZH2) is an important member of the epigenetic regulatory factor polycomb group proteins (PcG) and is abnormally expressed in a wide variety of tumors, including osteosarcoma. Scientists consider EZH2 as an attractive target for the treatment of osteosarcoma and have found many potential EZH inhibitors, such as GlaxoSmithKline 343 (GSK343). It has been reported that GSK343 can be used as an inhibitor in different types of cancer. This study demonstrated that GSK343 not only induced apoptosis by increasing cleaved Casp-3 and poly ADP-ribose polymerase (PARP) expression, but also induced autophagic cell death by inhibiting p62 expression. Apoptosis and autophagic cell death induced by GSK343 were confirmed by the high expression of cleaved caspase-3, LC3-II and transmission electron microscopy. GSK343 inhibited the expression of EZH2 and c-Myc. Additionally, GSK343 inhibited the expression of FUSE binding protein 1 (FBP1), which was identified by its regulatory effects on c-Myc expression. Since c-Myc is a common target of EZH2 and FBP1, and GSK343 inhibited the expression of these proliferation-promoting proteins, a mutual regulatory mechanism between EZH2 and FBP1 was proposed. The knockdown of EZH2 suppressed the expression of FBP1; similarly, the knockdown of FBP1 suppressed the expression of EZH2. These results suggest the mutual regulatory association between EZH2 and FBP1. The knockdown of either EZH2 or FBP1 accelerated the sensitivity of osteosarcoma cells to GSK343. Based on these results, this study clarified that GSK343, an EZH2 inhibitor, may have potential for use in the treatment of osteosarcoma. The underlying mechanisms of the effects of GSK343 are partly mediated by its inhibitory activity against c-Myc and its regulators (EZH2 and FBP1).
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PMID:GSK343 induces programmed cell death through the inhibition of EZH2 and FBP1 in osteosarcoma cells. 3165 Dec 9

Tumor microenvironment is a critical participant in the initiation, progression and drug resistance of carcinomas, including osteosarcoma. Notoginsenoside R1 (NGR1) is a proverbial active ingredient of the traditional Chinese medicine Panax notoginseng (PN) and possess undeniable roles in several cancers. Nevertheless, its function in osteosarcoma and tumor microenvironment remains elusive. In the current study, exposure to NGR1 dose-dependently inhibited osteosarcoma cell viability and migration, and induced apoptosis. Furthermore, osteosarcoma cells that were incubated with conditioned medium (CM) from bone marrow mesenchymal stem cells (BMSCs) exhibited greater proliferation, migration capacity and MMP-2 and MMP-9 expression relative to control cells, which was reversed when BMSCs were treated with NGR1. Notably, administration with NGR1 antagonized CM-evoked doxorubicin resistance in osteosarcoma cells by decreasing cell viability and increasing cell apoptosis and caspase-3/9 activity. Mechanically, NGR1 suppressed IL-6 secretion from BMSCs, as well as the subsequent activation of the JAK2/STAT3 signaling in osteosarcoma cells. In addition, blocking the JAK2 pathway by its antagonist AG490 reversed CM-induced osteosarcoma cell proliferation, migration and doxorubicin resistance. Moreover, exogenous supplementation with IL-6 engendered not only the reactivation of the JAK2/STAT3 signaling but also muted NGR1-mediated efficacy against osteosarcoma cell malignancy and doxorubicin resistance. Collectively, NGR1 may directly restrain osteosarcoma cell growth and migration, or indirectly antagonize MSC-evoked malignancy and drug resistance by interdicting IL-6 secretion-evoked activation of the JAK2/STAT3 pathway. Consequently, the current study may highlight a promising therapeutic strategy against osteosarcoma by regulating tumor cells and the tumor microenvironment.
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PMID:Notoginsenoside R1 counteracts mesenchymal stem cell-evoked oncogenesis and doxorubicin resistance in osteosarcoma cells by blocking IL-6 secretion-induced JAK2/STAT3 signaling. 3312 83


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