Small Molecule-Based Promotion of PKCα-Mediated β-Catenin Degradation Suppresses the Proliferation of CRT-Positive Cancer Cells 英文参考文献.docVIP

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Small Molecule-Based Promotion of PKCα-Mediated β-Catenin Degradation Suppresses the Proliferation of CRT-Positive Cancer Cells 英文参考文献.doc

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Small Molecule-Based Promotion of PKCα-Mediated β-Catenin Degradation Suppresses the Proliferation of CRT-Positive Cancer Cells 英文参考文献

Small Molecule-Based Promotion of PKCa-Mediated b-Catenin Degradation Suppresses the Proliferation of CRT-Positive Cancer Cells JungsugGwak1,2,Jee-HyunLee3,Young-HwaChung4,Gyu-YongSong3*,SangtaekOh1,2* 1Department of Advanced Fermentation Fusion Science and Technology, Kookmin University, Seoul, Republic of Korea, 2PharmacoGenomics Research Center, Inje University, Busan, Republic of Korea, 3College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea, 4WCU, Department of Cogno-Mechatronics Engineering,PusanNationalUniversity,Busan,RepublicofKorea Abstract Aberrant accumulationof intracellularb-cateninis awell recognizedcharacteristic of severalcancers, includingprostate, colon,andlivercancers,andisapotentialtargetfordevelopmentofanticancertherapeutics.Here,weusedcell-basedsmall molecule screening to identify CGK062 as an inhibitor of Wnt/b-catenin signaling. CGK062 promoted protein kinase Ca (PKCa)-mediated phosphorylation of b-catenin at Ser33/Ser37, marking it for proteasomal degradation. This reduced intracellular b-catenin levels and consequently antagonized b-catenin response transcription (CRT). Pharmacological inhibition or depletion of PKCaabrogated CGK062-mediated phosphorylation and degradation of b-catenin. In addition, CGK062 repressed the expression of the genes encoding cyclin D1, c-myc, and axin-2, b-catenin target genes, and thus inhibitedthegrowthofCRT-positivecancercells.Furthermore,treatmentofnudemicebearingPC3xenografttumorswith CGK062 at doses of 50mg/kg and 100mg/kg (i.p.) significantly suppressed tumor growth. Our findings suggest that CGK062 exerts its anticancer activity by promoting PKCa-mediated b-catenin phosphorylation/degradation. Therefore, CGK062hassignificanttherapeuticpotentialforthetreatmentofCRT-positivecancers. Citation:GwakJ,LeeJ-H,ChungY-H,SongG-Y,OhS(2012)Small Molecule-Based Promotion of PKCa-Mediated b-Catenin Degradation Suppresses the Proliferation of CRT-Positive Cancer Cells. PLoS ONE 7(10): e4