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In Vitro Antimetastatic Effect of Phosphatidylinositol 3-Kinase Inhibitor ZSTK474 on Prostate Cancer PC3 Cells
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin 300070, China
Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 17 February 2013; in revised form: 28 May 2013 / Accepted: 19 June 2013 / Published: 28 June 2013
Abstract: Tumor metastasis is the main cause of lethality of prostate cancer, because conventional therapies like surgery and hormone treatment rarely work at this stage. Tumor cell migration, invasion and adhesion are necessary processes for metastasis. By providing nutrition and an escape route from the primary site, angiogenesis is also required for tumor metastasis. Phosphatidylinositol 3-kinases (PI3Ks) are well known to play important roles in tumorigenesis as well as metastasis. ZSTK474 is a specific PI3K inhibitor developed for solid tumor therapy. In the present report, antimetastatic activities of ZSTK474 were investigated in vitro by determining the effects on the main metastatic processes. ZSTK474 exhibited inhibitory effects on migration, invasion and adhesive ability of prostate cancer PC3 cells. Furthermore, ZSTK474 inhibited phosphorylation of Akt substrate-Girdin, and the secretion of matrix metalloproteinase (MMP), both of which were reported to be closely involved in migration and invasion. On the other hand, ZSTK474 inhibited the expression of HIF-1α and the secretion of vascular endothelial growth factor (VEGF), suggesting its potential antiangiogenic activity on PC3 cells. Moreover, we demonstrated the antiangiogenesis by determining the effect of ZSTK474-reduced VEGF on tube formation of human umbilical vein endothelial cells (HUVECs). In conclusion, ZSTK474 was demonstrated to have potential in vitro antimetastatic effects on PC3 cells via dual mechanisms: inhibition of metastatic processes including cell migration, invasion and adhesion, and antiangiogenesis via blockade of VEGF secretion.
Keywords: phosphatidylinositol 3-kinase inhibitor; antimetastasis; ZSTK474; PC3; Girdin; VEGF
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Zhao, W.; Guo, W.; Zhou, Q.; Ma, S.-N.; Wang, R.; Qiu, Y.; Jin, M.; Duan, H.-Q.; Kong, D. In Vitro Antimetastatic Effect of Phosphatidylinositol 3-Kinase Inhibitor ZSTK474 on Prostate Cancer PC3 Cells. Int. J. Mol. Sci. 2013, 14, 13577-13591.
Zhao W, Guo W, Zhou Q, Ma S-N, Wang R, Qiu Y, Jin M, Duan H-Q, Kong D. In Vitro Antimetastatic Effect of Phosphatidylinositol 3-Kinase Inhibitor ZSTK474 on Prostate Cancer PC3 Cells. International Journal of Molecular Sciences. 2013; 14(7):13577-13591.
Zhao, Wennan; Guo, Wenzhi; Zhou, Qianxiang; Ma, Sheng-Nan; Wang, Ran; Qiu, Yuling; Jin, Meihua; Duan, Hong-Quan; Kong, Dexin. 2013. "In Vitro Antimetastatic Effect of Phosphatidylinositol 3-Kinase Inhibitor ZSTK474 on Prostate Cancer PC3 Cells." Int. J. Mol. Sci. 14, no. 7: 13577-13591.