Discrete functions of GSK3α and GSK3β isoforms in prostate tumor growth and micrometastasis

被引:35
作者
Gao, Fei [1 ,2 ]
Al-Azayzih, Ahmad [1 ,2 ,3 ]
Somanath, Payaningal R. [1 ,2 ,4 ,5 ]
机构
[1] Univ Georgia, Coll Pharm, Clin & Expt Therapeut, Augusta, GA 30912 USA
[2] Charlie Norwood VA Med Ctr, Augusta, GA USA
[3] Jordan Univ Sci & Technol, Coll Pharm, Irbid, Jordan
[4] Georgia Regents Univ, Vasc Biol Ctr, Dept Med, Augusta, GA USA
[5] Georgia Regents Univ, Ctr Canc, Augusta, GA USA
基金
美国国家卫生研究院;
关键词
GSK3; alpha; beta; invasion; micrometastasis; prostate cancer; GLYCOGEN-SYNTHASE KINASE-3; NF-KAPPA-B; BETA-CATENIN; CANCER CELLS; E-CADHERIN; PANCREATIC-CANCER; SUPPRESSOR GENE; BLADDER-CANCER; IN-VIVO; EXPRESSION;
D O I
10.18632/oncotarget.3335
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Isoform specific function of glycogen synthase kinase-3 (GSK3) in cancer is not well defined. We report that silencing of GSK3 alpha, but not GSK3 beta expression inhibited proliferation, survival and colony formation by the PC3, DU145 and LNCaP prostate cancer cells, and the growth of PC3 tumor xenografts in athymic nude mice. Silencing of GSK3 alpha, but not GSK3 beta resulted in reduced proliferation and enhanced apoptosis in tumor xenografts. ShRNA-mediated knockdown of GSK3 alpha and GSK3 beta equally inhibited the ability of prostate cancer cells to migrate and invade the endothelial-barrier in vitro, and PC3 cell micrometastasis to lungs in vivo. Mechanistically, whereas silencing GSK3 alpha resulted in increased expression of pro-apoptotic markers cleaved caspase-3 and cleaved caspase-9 in LNCaP, PC3 and DU145 cells, silencing GSK3 beta resulted in the inhibition of cell scattering, establishment of cell-cell contacts, increased expression and membrane localization of beta-catenin, and reduced expression of epithelial to mesenchymal transition (EMT) markers such as Snail and MMP-9. This indicated the specific role of GSK3 beta in EMT, acquisition of motility and invasive potential. Overall, our data demonstrated the isoform specific role of GSK3 alpha and GSK3 beta in prostate cancer cells in vitro, and tumor growth and micrometastasis in vivo, via distinct molecular and cellular mechanisms.
引用
收藏
页码:5947 / 5962
页数:16
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