Targeting Src-mediated Tyr216 phosphorylation and activation of GSK-3 in prostate cancer cells inhibit prostate cancer progression in vitro and in vivo

被引:57
作者
Goc, Anna [1 ,2 ]
Al-Husein, Belal [1 ,2 ]
Katsanevas, Katerina [1 ]
Steinbach, Alison [1 ]
Lou, Uvette [1 ]
Sabbineni, Harika [1 ,2 ]
DeRemer, David L. [1 ]
Somanath, Payaningal R. [1 ,2 ,3 ,4 ]
机构
[1] Univ Georgia, Coll Pharm, Augusta, GA USA
[2] Charlie Norwood VA Med Ctr, Augusta, GA USA
[3] Georgia Regents Univ, Ctr Canc, Dept Med, Augusta, GA USA
[4] Georgia Regents Univ, Vasc Biol Ctr, Augusta, GA USA
基金
美国国家卫生研究院;
关键词
Src; GSK-3; Tyr-216; prostate cancer; dasatinib; GLYCOGEN-SYNTHASE KINASE-3-BETA; FACTOR-KAPPA-B; KINASE; 3-BETA; PANCREATIC-CANCER; BETA-CATENIN; TYROSINE; GROWTH; INACTIVATION; GSK3-BETA; PATHWAY;
D O I
10.18632/oncotarget.1770
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 GSK3 activation in prostate cancer cells. Our data show that Src, a non-receptor tyrosine kinase is responsible for (Y216)GSK-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 (Y216)GSK-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 (Y216)GSK-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 (Y216)GSK-3 phosphorylation and activation in prostate cancer cells and reveal the potential benefits of targeting Src-GSK-3 axis using drugs such as dasatinib.
引用
收藏
页码:775 / 787
页数:13
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