Inositol hexaphosphate inhibits growth and induces G1 arrest and apoptotic death of androgen-dependent human prostate carcinoma LNCaP cells

被引:62
作者
Agarwal, C [1 ]
Dhanalakshmi, S [1 ]
Singh, RP [1 ]
Agarwal, R [1 ]
机构
[1] Univ Colorado, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci,Canc Ctr, Denver, CO 80262 USA
来源
NEOPLASIA | 2004年 / 6卷 / 05期
关键词
inositol hexaphosphate; prostate cancer prevention; apoptosis; cell cycle; cyclin-dependent kinase inhibitor;
D O I
10.1593/neo.04232
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Prostate cancer (PCA) is the most common invasive malignancy and the second leading cause of cancer-related deaths in the US male population. One approach to control this malignancy is its preventive intervention by dietary agents. Inositol hexaphosphate (IP6), a dietary constituent, has shown promising efficacy against various cancers; however, limited studies have been performed with IP6 against PCA. Here, we investigated the growth-inhibitory effect and associated mechanisms of IP6 in androgen-dependent human prostate carcinoma LNCaP cells. IP6 treatment of cells resulted in a strong growth inhibition and an increase in G1 cell population. In mechanistic studies, IP6 resulted in an increase in cyclin-dependent kinase inhibitors (CDKIs) Cip1/p21 and Kip1/p27 levels, together with a decrease in cyclin-dependent kinase (CDK) 4 and cyclin D1 protein levels. An increase in CDKI levels by IP6 also led to a concomitant increase in their interactions with CDK2 and CDK4, together with a strong decrease in the kinase activity of both CDKs. Downstream in CDKI-CDK-cyclin cascade, consistent with its inhibitory effect on CDK kinase activity, IP6 treatment of cells increased hypophosphorylated levels of retinoblastoma (Rb) with a decrease in Rb phosphorylation at serine 780,807, and 811 sites, and caused a moderate to strong decrease in the levels of transcription factors E2F1, E2F4, and E2F5. In other studies, IP6 caused a dose- and a time-dependent apoptotic death of LNCaP cells, and a decrease in Bcl2 levels, causing a strong increase in Bax versus Bcl2 ratio, as well as an inhibition of constitutively active AKT phosphorylation. Taken together, these molecular alterations provide an insight into IP6-caused growth inhibition, G1 arrest, and apoptotic death of human prostate carcinoma LNCaP cells. Because early clinical PCA growth is an androgen-dependent response, the results of the present study employing androgen-dependent LNCaP cells suggest that IP6 has promise and potential to be effective against PCA.
引用
收藏
页码:646 / 659
页数:14
相关论文
共 87 条
[1]   Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents [J].
Agarwal, R .
BIOCHEMICAL PHARMACOLOGY, 2000, 60 (08) :1051-1059
[2]   Promoter activation and following induction of the p21/WAF1 gene by flavone is involved in G1 phase arrest in A549 lung adenocarcinoma cells [J].
Bai, FL ;
Matsui, T ;
Ohtani-Fujita, N ;
Matsukawa, Y ;
Ding, Y ;
Sakai, T .
FEBS LETTERS, 1998, 437 (1-2) :61-64
[3]   INOSITOL-PHOSPHATE-INDUCED ENHANCEMENT OF NATURAL-KILLER CELL-ACTIVITY CORRELATES WITH TUMOR SUPPRESSION [J].
BATEN, A ;
ULLAH, A ;
TOMAZIC, VJ ;
SHAMSUDDIN, AM .
CARCINOGENESIS, 1989, 10 (09) :1595-1598
[4]   Bifurcation of lipid and protein kinase signals of PI3Kγ to the protein kinases PKB and MAPK [J].
Bondeva, T ;
Pirola, L ;
Bulgarelli-Leva, G ;
Rubio, I ;
Wetzker, R ;
Wymann, MP .
SCIENCE, 1998, 282 (5387) :293-296
[5]   The epidemiology of prostate cancer [J].
Boyle, P ;
Severi, G ;
Giles, GG .
UROLOGIC CLINICS OF NORTH AMERICA, 2003, 30 (02) :209-+
[6]   New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase AKT pathway [J].
Cantley, LC ;
Neel, BG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (08) :4240-4245
[7]  
Carson JP, 1999, CANCER RES, V59, P1449
[8]   Interactive suppression of aberrant crypt foci induced by azoxymethane in rat colon by phytic acid and green tea [J].
Challa, A ;
Rao, DR ;
Reddy, BS .
CARCINOGENESIS, 1997, 18 (10) :2023-2026
[9]  
CHEN YQ, 1995, CANCER RES, V55, P4536
[10]  
Cheng L, 2000, CLIN CANCER RES, V6, P1896