Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ginkgetin, a biflavone from Ginkgo biloba leaves, is known to exhibit antiinflammatory, antifungal, neuroprotective, and antitumor activities, but its precise mechanism of action has not been fully elucidated. Because the aberrant activation of STAT3 has been linked with regulation of inflammation, proliferation, invasion, and metastasis of tumors, we hypothesized that ginkgetin modulates the activation of STAT3 in tumor cells. We found that ginkgetin clearly suppressed constitutive phosphorylation of STAT3 through inhibition of the activation of upstream JAK1 and c-Src kinases and nuclear translocation of STAT3 on both A549 and FaDu cells. Treatment with sodium pervanadate reversed the ginkgetin-induced down-modulation of STAT3, thereby indicating a critical role for a PTP. We also found that ginkgetin strongly induced the expression of the SHP-1 and PTEN proteins and its mRNAs. Further, deletion of SHP-1 and PTEN genes by siRNA suppressed the induction of SHP-1 and PTEN, and reversed the inhibition of STAT3 activation. Ginkgetin induced apoptosis as characterized by an increased accumulation of cells in subG1 phase, positive Annexin V binding, loss of mitochondrial membrane potential, down-regulation of STAT3-regulated gene products, and cleavage of PARP. Overall, ginkgetin abrogates STAT3 signaling pathway through induction of SHP-1 and PTEN proteins, thus attenuating STAT3 phosphorylation and tumorigenesis.
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PMID:Ginkgetin Blocks Constitutive STAT3 Activation and Induces Apoptosis through Induction of SHP-1 and PTEN Tyrosine Phosphatases. 2705 88

The purpose of present study was to investigate anti-tumor activity of Ginkgetin (GK) and its mechanism of action in breast cancer. The effects of GK on growth of human breast cancer cell lines MDA-MB-231, BT-474 and MCF-7 were examined by MTT assay. Cells apoptosis in MCF-7 cells were analyzed by TUNEL staining and annexin-V and propidium iodide double staining. The effects of GK on expression of apoptotic associated proteins and mitogen-activated protein kinases (MAPKs) were determined by western blotting. The results showed that GK significantly inhibited proliferation of MDA-MB-231, BT-474 and MCF-7 cells in vitro with time and dose dependent manners and induced apoptosis in MCF-7 cells. GK treatment obviously induced the tumor cells apoptosis and inhibited tumor growth in the MCF-7 xenograft nude mice. GK increased expression of Bax, cleaved-caspase-3, cleaved-caspase-8, cleaved-caspase-9, cleaved-PARP, and decreased the levels of Bcl-2 and survivin in MCF-7 cells. Moreover, GK treatment up-regulated expression of phospho extracellular-related kinase (p-ERK), p-p38 and phospho Jun-amino-terminal kinase (p-JNK) in MCF-7 cells in vitro, and increased numbers of p-p38, p-JNK and p-ERK positive cells in the tumor tissue in vivo. Strikingly, treatment of p38 inhibitor (or JNK inhibitor; ERK inhibitor) significantly prevented GK induced growth inhibition and apoptosis in MCF-7 cells. Collectively, our data exhibit GK exerts well anticancer effects in breast cancer cells, which at least in part, is via activation of the MAPKs. Our results provide a new approach for the treatment of breast cancer.
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PMID:Ginkgetin inhibits growth of breast carcinoma via regulating MAPKs pathway. 2903 Dec 4