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Establishment of a Model for Screening of Protein Kinase C Inhibitor and the Screening, Evaluation of the Active Compound

Author: LiLi
Tutor: GengMeiYu
School: Ocean University of China
Course: Pharmacognosy
Keywords: Protein kinase C Metastasis Tumor Inhibitor
CLC: R96
Type: Master's thesis
Year: 2009
Downloads: 139
Quote: 0
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Abstract


Protein kinase C is a calcium-dependent and phospho-lipid-activated protein kinase first described by Nishizuka and his coworkers. It plays an important role in the intra-cellular signal transduction. The PKC family consists of at least eleven members, divided into four subgroups: classical PKCs, novel PKCs, atypical PKCs, and PKCμ.Protein kinase C (PKC) rocketed to the forefront of the cancer research field in the early 1980s with its identification as the target of the phorbol esters and a lot of succedent researches validate its key role in carcinogenesis and metastasis. Therefore, PKC is the potential molecular target to develop the treatments of cancer. PKCαis ubiquitously expressed in many tissues and has been associated with cell proliferation, cell-cycle regulation and cell invasion and metastasis; There is a large body of evidence linking PKCβⅡto proliferation, invasion and angiogenesis. Whereas PKCδhas been linked with the induction of the pro-tumorigenic sonic hedgehog (SHH) signalling and Wnt signalling. Therefore, PKCα, PKCβⅡand PKCδhave very close relationship with tumor. Currently several specific inhibitors and oligonucleotides inhibiting cPKCs have entered clinical trials, for example, Aprinocarsen, a selective inhibitor of PKCα, Enzastaurin, a selective inhibitor of PKCβ, but many of the PKC inhibitors being discarded at clinical trials. Therefore, the establishment of the screening model for subtype-specific inhibitor targeting PKCα, PKCβⅡor PKCδwill provide the technology platform for the development of anti-cancer drugs targeting PKC.Based on the above research background, this paper aims to establish the molecular level and cell level screening model targeting PKCα, PKCβⅡor PKCδrespectively using fluorescence polarization technology and transfection, proceed the compounds screening and evaluate the tumor cell behavior effect of the active compound. This paper will provide experimental basis for research and development anti-cancer drugs targeting PKC1. Establishment of the molecular level model for protein kinase C inhibitor screening .Established the molecular level model for protein kinase C inhibitor screening using fluorescence polarization technology, verified the screening model with the PKC inhibitor staurosporine and screened the compounds. The results show that we established a stable screening model for protein kinase C inhibitor and obtained an active compound which inhibited PKCβⅡ.2. Establishment of the cell level model for protein kinase C inhibitor screening and evaluated the effect of the active compound on tumor cell behavior.We obtained PKCα, PKCβⅡor PKCδhigh expressing cell line respectively using p-BABE retrovirus vectors. Western-blot and immunofluorescence chemistry analysis showed that there was a great expression of target proteins. We verified the credibility of the cell level model with the PKC activator PMA and the inhibitor staurosporine and analyzed the effect of the active compound on tumor cell behavior.

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