Abstract
Recent studies suggest a positive correlation between glycogen synthase kinase-3 (GSK-3) activation and tumor growth. Currently, it is unclear how both Akt that inhibits GSK-3 and active GSK-3 are maintained concurrently in tumor cells. We investigated the role of GSK-3 and the existence of an Akt-resistant pathway for GSK-3 activation in prostate cancer cells. Our data show that Src, a non-receptor tyrosine kinase is responsible for Y216GSK-3 phosphorylation leading to its activation even when Akt is active. Experiments involving mouse embryonic fibroblasts lacking cSrc, Yes and Fyn, as well as Src activity modulation in prostate cancer cells with constitutively active (CA-Src) and dominant negative Src (DN-Src) plasmids demonstrated the integral role of Src in Y216GSK-3 phosphorylation and activity modulation. Inhibition of GSK-3 with SB415286 in PC3 cells resulted in impaired motility, proliferation and colony formation. Treatment of PC3 cells with the Src inhibitor dasatinib reduced Y216GSK-3 phosphorylation and inhibited proliferation, invasion and micrometastasis in vitro. Dasatinib treatment of athymic nude mice resulted in impaired growth of PC3 cell tumor xenograft. Together, we provide novel insight into the Src-mediated Y216GSK-3 phosphorylation and activation in prostate cancer cells and reveal the potential benefits of targeting Src-GSK-3 axis using drugs such as dasatinib.
Highlights
Prostate cancer is the second leading cause of cancer-related death among men in the United States
These results indicated that Glycogen synthase kinase 3 (GSK-3) activity is necessary for prostate cancer cell tumorigenic and invasive properties in vitro
Our data indicated that inhibition of GSK-3 activity as a result of treatment with GSK-3 specific inhibitor SB415286 or SiRNAmediated knockdown of GSK-3 in murine TRAMP (TR-C2N) and human (PC3) invasive prostate cancer cell lines lead to impaired prostate cancer cell motility, proliferation, survival, invasion and colony formation in vitro
Summary
Prostate cancer is the second leading cause of cancer-related death among men in the United States. Since Akt and GSK-3 activities are known to be regulated reciprocally, it is not clear how these two kinases can be simultaneously present in their active form in cancer cells This demands further investigation on the specific role of GSK-3 in cancer cells and in order to characterize the existence of an Akt-independent mechanism of GSK-3 activity regulation in multiple cancers. Due to its importance in numerous of cellular functions, GSK-3 activity is tightly regulated via phosphorylation at multiple serine, threonine and tyrosine residues by various kinases. We investigated if Src is involved in the Y216 phosphorylation and GSK3 activity regulation, and characterized the efficacy of targeting Src-GSK-3 pathway using pharmacological inhibitors for prostate cancer therapy. We demonstrate that GSK-3β activation by Src-mediated Y216 phosphorylation augments prostate cancer cell function in vitro and tumor xenograft growth in vivo. Our study unveils the potential benefits of dasatinib in the management of prostate cancer by inhibiting Src-GSK-3β pathway, further preclinical and clinical validation is desirable
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