Oncotarget

Research Papers:

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

Fei Gao, Ahmad Al-Azayzih and Payaningal R. Somanath _

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Oncotarget. 2015; 6:5947-5962. https://doi.org/10.18632/oncotarget.3335

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Abstract

Fei Gao1, Ahmad Al-Azayzih1,2 and Payaningal R. Somanath1,3

1 Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA

2 College of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan

3 Department of Medicine, Vascular Biology Center and Cancer Center, Georgia Regents University, Augusta, GA, USA

Correspondence to:

Payaningal R. Somanath, email:

Keywords: GSK3α, GSK3β, invasion, micrometastasis, prostate cancer

Received: September 24, 2014 Accepted: January 04, 2015 Published: January 21, 2015

Abstract

Isoform specific function of glycogen synthase kinase-3 (GSK3) in cancer is not well defined. We report that silencing of GSK3α, but not GSK3β 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 GSK3α, but not GSK3β resulted in reduced proliferation and enhanced apoptosis in tumor xenografts. ShRNA-mediated knockdown of GSK3α and GSK3β 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 GSK3α resulted in increased expression of pro-apoptotic markers cleaved caspase-3 and cleaved caspase-9 in LNCaP, PC3 and DU145 cells, silencing GSK3β resulted in the inhibition of cell scattering, establishment of cell-cell contacts, increased expression and membrane localization of β-catenin, and reduced expression of epithelial to mesenchymal transition (EMT) markers such as Snail and MMP-9. This indicated the specific role of GSK3β in EMT, acquisition of motility and invasive potential. Overall, our data demonstrated the isoform specific role of GSK3α and GSK3β in prostate cancer cells in vitro, and tumor growth and micrometastasis in vivo, via distinct molecular and cellular mechanisms.


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