Dihydroartemisinin suppresses the tumorigenesis and cycle progression of colorectal cancer by targeting CDK1/CCNB1/PLK1 signaling
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ABSTRACT:
PROVIDER: PRJNA767804 | ENA |
REPOSITORIES: ENA
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Project description:Dihydroartemisinin (DHA), a well-known antimalarial drug, has been widely investigated as its anti-tumor effects in multiple malignancies. However, its effects and regulatory mechanisms in colorectal cancer (CRC) are still unproved. In this study, the in vitro experiments including CCK8, EdU, Transwell, flow cytometry analyses and in vivo tumorigenesis model were conducted to assess the effects of DHA on the bio-behaviors of CRC cells. Additionally, RNA-seq combined with gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses was used to obtain the targets of DHA and these were verified by molecular docking, qRT-PCR and Western blot. As a result, we found that DHA significantly suppressed the proliferation, DNA synthesis and invasive capabilities, and induced cell apoptosis and cell cycle arrest in HCT116, DLD1 and RKO cells in vitro and in vivo. Further analyses indicated that the targets of DHA were predominantly enriched in cell cycle-associated pathways, including CDK1, CCNB1 and PLK1, and DHA could bind with CDK1/CCNB1 complex and inhibit the activation of CDK1/CCNB1/PLK1 signaling. Moreover, cucurbitacin E, a specific inhibitor of CDK1/CCNB1 axis enhanced the inhibitory effects of DHA on DNA synthesis and colony formation in HCT116 and DLD1 cells. In short, DHA could suppress the tumorigenesis and cycle progression of CRC cells by targeting CDK1/CCNB1/PLK1 signaling.
2021-10-04 | GSE185141 | GEO
Project description:Dihydroartemisinin (DHA), a well-known antimalarial drug, has been widely investigated for its antitumor effects in multiple malignancies. However, its effects and regulatory mechanisms in colorectal cancer (CRC) are still unproved. In this study, in vitro experiments including CCK8, EdU, Transwell, and flow cytometry analyses and an in vivo tumorigenesis model were conducted to assess the effects of DHA on the bio-behaviors of CRC cells. Additionally, RNA-seq combined with gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses was used to obtain the targets of DHA, and these were verified by molecular docking, qRT-PCR, and Western blotting. As a result, we found that DHA significantly suppressed the proliferation, DNA synthesis, and invasive capabilities and induced cell apoptosis and cell cycle arrest in HCT116, DLD1, and RKO cells in vitro and in vivo. Further analyses indicated that the targets of DHA were predominantly enriched in cell cycle-associated pathways, including CDK1, CCNB1, and PLK1; and DHA could bind with the CDK1/CCNB1 complex and inhibit the activation of CDK1/CCNB1/PLK1 signaling. Moreover, cucurbitacin E, a specific inhibitor of the CDK1/CCNB1 axis, enhanced the inhibitory effects of DHA on DNA synthesis and colony formation in HCT116 and DLD1 cells. In short, DHA could suppress the tumorigenesis and cycle progression of CRC cells by targeting CDK1/CCNB1/PLK1 signaling.
| S-EPMC8592930 | biostudies-literature
Project description:The fidelity of chromosome segregation in mitosis is safeguarded by the precise regulation of kinetochore microtubule (k-MT) attachment stability. Previously, we demonstrated that Cyclin A/Cdk1 destabilizes k-MT attachments to promote faithful chromosome segregation. Here, we use quantitative phosphoproteomics to identify 156 Cyclin A/Cdk1 substrates in prometaphase. One Cyclin A/Cdk1 substrate is myosin phosphatase targeting subunit 1 (MYPT1), and we show that MYPT1 localization to kinetochores depends on Cyclin A/Cdk1 activity and that MYPT1 destabilizes k-MT attachments by negatively regulating Plk1 at kinetochores. Thus, Cyclin A/Cdk1 phosphorylation primes MYPT1 for Plk1 binding. Interestingly, priming of PBIP1 by Plk1 itself (self-priming) increased in MYPT1-depleted cells showing that MYPT1 provides a molecular link between the processes of Cdk1-dependent priming and self-priming of Plk1 substrates. These data demonstrate cross-regulation between Cyclin A/Cdk1-dependent and Plk1-dependent phosphorylation of substrates during mitosis to ensure efficient correction of k-MT attachment errors necessary for high mitotic fidelity.
2017-12-01 | PXD008316 | Pride
Project description:Although 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to PI3K-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces Myc phosphorylation and protein accumulation. We show that PDK1-PLK1-Myc signaling is critical for cancer cell growth and survival and small molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting Myc-dependency. Intriguingly, PDK1-PLK1-Myc signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self renewal. Finally, we show that PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a compensatory Myc induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting Myc-associated tumorigenesis and therapeutic resistance. Gene expression profiling of Human Embryonic Kidney Cells (HEK-TERV) under different conditions: PMN, PDK1, MYC and E545K
2013-07-31 | E-GEOD-30669 | biostudies-arrayexpress
Project description:The Epstein-Barr virus nuclear antigen 2 (EBNA2) initiates and maintains the proliferation of infected B cells. In search of additional cellular strategies, that control EBNA2 function, we have performed a label-free mass spectrometry-based quantification of cellular proteins in EBNA2 immuno-precipitates and found polo-like kinase 1 (PLK1) to be bound to EBNA2. EBNA2/PLK1 complex formation is strongly enforced by EBNA2 S379 phosphorylation catalyzed by the mitotic CYCLIN B/CDK1 complex.
2021-08-22 | PXD022970 | Pride
Project description:Although 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to PI3K-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces Myc phosphorylation and protein accumulation. We show that PDK1-PLK1-Myc signaling is critical for cancer cell growth and survival and small molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting Myc-dependency. Intriguingly, PDK1-PLK1-Myc signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self renewal. Finally, we show that PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a compensatory Myc induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting Myc-associated tumorigenesis and therapeutic resistance.
2013-07-31 | GSE30669 | GEO
Project description:Transcriptional profiling of mouse aortas comparing control wild-type animals with aortas from three different Plk1(+/-) mice. Goal was to determine the effects of Plk1 haploinsufficiency in aorta expression profiles.
2017-07-01 | GSE85199 | GEO
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell-derived sarcomas that are sporadic or associated with NF1 gene mutations. Traditional therapies are `usually ineffective for treating MPNSTs, so new targets need to be identified for the treatment of MPNSTs. In the present study, the role of the mitochondrial translocator protein (TSPO) in the regulation of cell proliferation and the cell cycle in MPNSTs was investigated. TSPO expression was lower in MPNSTs than in NFs. Loss-of-function experiments revealed that TSPO deficiency promoted MPNST cell growth, migration, and invasion and influenced the cell cycle in vitro and in vivo. In addition, TSPO depletion suppressed cell apoptosis by downregulating the expression of caspase-3, caspase-8, HSP60, p27, p53, and BCL-2 and suppressed the cell cycle by upregulating CDK1, CDK2, CCNB1 and CCNA2. Furthermore, CDK1 was determined to be an upstream target of TSPO-mediated regulation via RNA-seq, qPCR, and Western blotting. Specifically, depletion of CDK1 weakened the effect of TSPO deficiency on cell proliferation and migration. More importantly, CDK1 knockdown induced significant cell cycle arrest in the G2/M phase. In summary, TSPO deficiency regulates the cell cycle in MPNSTs by targeting CDK1, which may be an effective molecular target for prognosis evaluation and treatment.
2024-06-26 | GSE270880 | GEO
Project description:Polo-like kinase 1 (PLK1) is a serine/threonine kinase required for mitosis and cytokinesis. As cancer cells are often hypersensitive to partial PLK1 inactivation, chemical inhibitors of PLK1 have been developed and tested in clinical trials. However, these molecules alone were not completely effective. PLK1 promotes numerous molecular and cellular events in the cell division cycle. To date, it is unclear which of these events most crucially depend on PLK1 activity. We used a CRISPR-based genome-wide screening strategy to identify genes whose inactivation enhances cell proliferation defects upon partial chemical inhibition of PLK1. Genes identified encode proteins that are functionally linked to PLK1 in multiple ways. Among them, factors that promote centromere and kinetochore function were clearly enriched. In particular, inactivation of the kinesin KIF18A or SKA1 in PLK1-compromised cells results in mitotic defects, activation of the spindle assembly checkpoint and nuclear reassembly defects. Our results suggest that functions of PLK1 at kinetochores are most sensitive to its inhibition, and point at KIF18A as a possible target for combinatorial therapies using existing PLK1 inhibitors.
2023-10-02 | GSE228155 | GEO
Project description:Analysis of MCF7 breast cancer cells treated with estadiol for 6 h in presence or absence of the specific PLK1 inhibitor BI2536. Together with CHIP and global phosphoproteome data, the results demonstrate a key role of PLK1 in the estrogen receptor-mediated gene response. Hormone-deprived MCF7 cells were pretreated with BI2536 or vehicle (DMSO) followed by induction with estradiol (E2) or vehicle (ethanol). RNA of each condition was analysed in triplicate on an Agilent Human genome 4x44k v2 microarray [note: MCF7_DMSO_E2_rep3 sample was a clear technical outlier (poor hybridization), and was therefore excluded from the further analysis/this record].
2014-01-01 | E-GEOD-46856 | biostudies-arrayexpress