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p21/Cip1 and p27/Kip1 Are Essential Molecular Targets of Inositol Hexaphosphate for Its Antitumor Efficacy against Prostate Cancer

¹ Department of Pharmaceutical Sciences, School of Pharmacy, ² Department of Biochemistry and Molecular Genetics, University of Colorado Denver, ³ University of Colorado Cancer Center, Denver, Colorado; and ⁴ Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

Requests for reprints: Rajesh Agarwal, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, C238-P15, Research 2, 12700 E. 19th Ave., Aurora, CO 80045. Phone: 303-724-4055; Fax: 303-724-7266; E-mail: Rajesh.Agarwal{at}UCDenver.edu.

Key Words: inositol hexaphosphate • prostate cancer • p21/Cip1 • p27/Kip1 • cell cycle • apoptosis

Inositol hexaphosphate (IP6) causes G₁ arrest and increases cyclin-dependent kinase inhibitors p21/Cip1 and p27/Kip1 protein levels in human prostate cancer (PCa) DU145 cells lacking functional p53. However, whether cyclin-dependent kinase inhibitor I induction by IP6 plays any role in its antitumor efficacy is unknown. Herein, we observed that either p21 or p27 knockdown by small interfering RNA has no considerable effect on IP6-induced G₁ arrest, growth inhibition, and death in DU145 cells; however, the simultaneous knockdown of both p21 and p27 reversed the effects of IP6. To further confirm these findings both in vitro and in vivo, we generated DU145 cell variants with knockdown levels of p21 (DU-p21), p27 (DU-p27), or both (DU-p21+p27) via retroviral transduction of respective short hairpin RNAs. Knocking down p21 or p27 individually did not alter IP6-caused cell growth inhibition and G₁ arrest; however, their simultaneous ablation completely reversed the effects of IP6. In tumor xenograft studies, IP6 (2% w/v, in drinking water) caused a comparable reduction in tumor volume (40–46%) and tumor cell proliferation (26–28%) in DU-EV (control), DU-p21, and DU-p27 tumors but lost most of its effect in DU-p21+p27 tumors. IP6-caused apoptosis also occurred in a Cip/Kip-dependent manner because DU-p21+p27 cells were completely resistant to IP6-induced apoptosis both in cell culture and xenograft. Together, these results provide evidence, for the first time, of the critical role of p21 and p27 in mediating the anticancer efficacy of IP6, and suggest their redundant role in the antiproliferative and proapoptotic effects of IP6 in p53-lacking human PCa cells, both in vitro and in vivo. [Cancer Res 2009;69(3):1166–73]

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				M. Gu, S. Roy, K. Raina, C. Agarwal, and R. Agarwal Inositol Hexaphosphate Suppresses Growth and Induces Apoptosis in Prostate Carcinoma Cells in Culture and Nude Mouse Xenograft: PI3K-Akt Pathway as Potential Target Cancer Res., December 15, 2009; 69(24): 9465 - 9472. [Abstract] [Full Text] [PDF]