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.
Highlights
Glycogen synthase kinase-3 (GSK3) has assumed a very unique place in various signaling pathways, their precise role in various cellular processes still remains unclear
Since knocking down GSK3α in prostate cancer cells is much more effective in inhibiting prostate tumor growth and colonization compared to GSK3β, our study reveal that inhibition of GSK3α or even better, pharmacological inhibition of both glycogen synthase kinase-3 (GSK3) isoforms will be an effective strategy for prostate cancer therapy
A significant inhibition of cell growth was observed in GSK3β deficient PC3, DU145 and LNCaP cells, effect was modest when compared to the GSK3α deficient cells (Figure 1A-C)
Summary
Glycogen synthase kinase-3 (GSK3) has assumed a very unique place in various signaling pathways, their precise role in various cellular processes still remains unclear. Since GSK3 activity is inhibited by Akt-mediated phosphorylation at Serine 21 and Serine 9 in two different isoforms namely GSK3α and GSK3β respectively [5, 6], scientists believed that activation of GSK3 may likely suppress cancer progression. Recent reports indicated that inhibition of GSK3 activity has tumor suppressive effect on various cancers [7,8,9,10,11,12], raising the question how Akt and GSK3 can concurrently be active in cancers. Until today precise role of GSK3 in multiple cellular functions and clinical conditions is controversial, and isoform specific functions of GSK3 and their specific downstream targets in various cancers remain unclear
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