Abstract:
:Protein kinase C (PKC) designates a family of kinases that regulate many essential functions including cell growth and differentiation. The tight regulation of PKC activity is crucial for maintaining normal cellular proliferation and excessive activity leads to abnormal or uncontrolled cell growth. Recent reports indicate that malignant glioma cell lines express 100 to 1000-fold higher PKC activity when compared to non-neoplastic astrocytes. This high activity correlates well with the proliferation of tumor cells in vitro. We recently reported on the anti-proliferative properties of selective PKC inhibitors on the growth of U-373MG human astrocytoma cell line, and their ability to block mitogen-activated protein (MAP) kinase pathway activated by substance P (SP) neuropeptide receptor signaling via a PKC-dependent mechanism. Therefore, inhibiting PKC activity by selective PKC inhibitors may present a promising approach for improving astroglial brain tumor therapy. For this purpose, we constructed a high throughput model cell system to evaluate the efficacy of PKC inhibitors. This system is based on the measurement of light production in U-373MG cells stably transfected with the luciferase reporter gene whose expression depends on the transcriptional activation of GAL4-Elk1 fusion protein by enzyme components of the MAP kinase pathway and the upstream activation of PKC (PKC activation-->MAP kinases-->GAL4-Elk1 phosphorylation-->luciferase expression-->luciferase activity). In brief, we have demonstrated that the PKC activator 12-O-tetradecanoyl phorbol 13-acetate (TPA)-induced luciferase activity in this cell system is mediated via the MAP kinase pathway and can be blocked in the presence of MEK1 selective inhibitors (PD 098059 or U0126). We also demonstrated that TPA-induced luciferase activity in U-373MG stable clones can be blocked by PKC inhibitors (CGP 41251, Go 6976, and GF 109203X) in a concentration dependent manner. In contrast, epidermal growth factor (EGF)-induced luciferase activity, which is independent of PKC activation (Ras-->Raf-1-->MEK1-->MAP kinases-->GAL4-Elk1 phosphorylation-->luciferase expression-->luciferase activity) can only be blocked using a selective EGF receptor inhibitor (AG 1478). In conclusion, we have constructed a model cell system for the high throughput screening and identification of PKC inhibitors potentially active against astrocytoma cells in culture.
journal_name
Int J Oncoljournal_title
International journal of oncologyauthors
Sharif TR,Sharif Mdoi
10.3892/ijo.14.2.327subject
Has Abstractpub_date
1999-02-01 00:00:00pages
327-35issue
2eissn
1019-6439issn
1791-2423journal_volume
14pub_type
杂志文章abstract::The pituitary gland is an organ that functionally connects the hypothalamus with the peripheral organs. The pituitary gland is an important regulator of body homeostasis during development, stress, and other processes. Pituitary adenomas are a group of tumors arising from the pituitary gland: they may be subdivided in...
journal_title:International journal of oncology
pub_type: 杂志文章,评审
doi:10.3892/ijo.2017.4120
更新日期:2017-10-01 00:00:00
abstract::Gene amplification occurs frequently in human glioblastomas. We report the amplification and expression analysis of glioma amplified sequence 64 (GAS64) which was recently identified by microdissection mediated cDNA capture from the amplicon at 12q13-15. Herein we analyzed primary tumor tissues for amplification frequ...
journal_title:International journal of oncology
pub_type: 杂志文章
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更新日期:2002-01-01 00:00:00
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journal_title:International journal of oncology
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doi:10.3892/ijo.1.5.555
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journal_title:International journal of oncology
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更新日期:2015-11-01 00:00:00
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pub_type: 杂志文章
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journal_title:International journal of oncology
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doi:10.3892/ijo.8.5.875
更新日期:1996-05-01 00:00:00
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pub_type: 杂志文章
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更新日期:1996-03-01 00:00:00
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更新日期:2006-05-01 00:00:00
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pub_type: 杂志文章
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更新日期:2019-05-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章
doi:10.3892/ijo.2018.4554
更新日期:2018-11-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章
doi:10.3892/ijo.2018.4649
更新日期:2019-02-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章
doi:
更新日期:2005-07-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章
doi:10.3892/ijo.15.4.835
更新日期:1999-10-01 00:00:00
abstract::We investigated the clinical significance of the expression levels of matrix metalloproteinase 9 (MMP-9) in renal cell carcinoma (RCC). In addition, we validated the efficacy of pyrrole imidazole polyamide (PIP) targeting MMP-9 on inhibiting proliferation and invasion of RCC. We evaluated the expression levels of MMP-...
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pub_type: 杂志文章
doi:10.3892/ijo.2013.2073
更新日期:2013-11-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章
doi:
更新日期:2003-04-01 00:00:00
abstract::Mutations of p53 tumor suppressor gene increase with tumor progression in colorectal cancers. In this study, we examined the expressions of p33ING1, p14ARF, MDM2 and p21WAF1 mRNA in 25 advanced colorectal cancers by quantitative RT-PCR method, and compared the expression levels of p33ING1, p14ARF, p21WAF1 and MDM2 in ...
journal_title:International journal of oncology
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doi:
更新日期:2004-10-01 00:00:00
abstract::The inhibitory effects of macrolide antibiotics including clarithromycin (CAM) on autophagy flux have been reported. Although a macrolide antibiotic exhibits no cytotoxicity, its combination with bortezomib (BZ), a proteasome inhibitor, for the simultaneous blocking of the ubiquitin (Ub)‑proteasome and autophagy‑lysos...
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更新日期:2015-02-01 00:00:00
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pub_type: 杂志文章,评审
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journal_title:International journal of oncology
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更新日期:2005-01-01 00:00:00
abstract::TP53 gene, encoding tumor protein P53, is frequently inactivated in various types of human cancer, including colorectal, lung, and gastric cancer. Cancer cells with TP53 mutation acquire malignant potentials, such as selective growth advantage, genomic instability, resistance to apoptosis, and promotion of angiogenesi...
journal_title:International journal of oncology
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更新日期:2004-07-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章
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journal_title:International journal of oncology
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journal_title:International journal of oncology
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