This competitive renewal application is for continued funding to investigate the molecular mechanisms underlying the anticancer effects of apigenin on prostate cancer. During the previous funding period, we investigated the effects of apigenin on various protein kinases, the IGF-I growth axis, ?-Catenin and NF-(B signaling pathways in cell cultures, tumor xenografts and a genetically-modified mouse model of prostate cancer. We found that apigenin inhibits multiple signal transduction pathways;consequently, potential targets of apigenin action include phosphatidylinositol 3-kinase (PI3K), protein kinase B/Akt, classical MAPK/ERK1/2, and cyclin-dependent kinases. The dose range of apigenin that effectively inhibits these targets is similar to that which suppresses signaling and prostate tumorigenesis and is physiologically attainable in humans. In this renewal application, we hypothesize that I(B kinase: IKKa/? acts as a central hub in mediating the anticancer effects of apigenin on multiple signal transduction pathways. Our hypothesis is based upon our previously published findings and our preliminary data showing that i) IKK activity is upregulated in human prostate cancer and its putative precursor ii) apigenin inhibits IKK activity and its phosphorylation, iii) apigenin inhibits multiple signal transduction pathways, specifically, the IGF-I axis, PI3K-Akt, NF-(B and ?-Catenin pathways, and iv) the IKK complex exhibits regulatory effects on all of these distinct signaling pathways. To test this hypothesis, we will use state-of-the-art techniques, including 1H NMR, X-ray crystallography, and advanced molecular biology procedures, and our studies will be performed on knock-in and knockout cell cultures and on transgenic (TRAMP) mice. Our proposed specific aims include investigation of i) the role of IKKa/? in cell transformation and the inhibitory activity of apigenin, ii) the role of IKKa on maspin suppression and its modulation by apigenin, iii) the role of IKK? on activity and cellular distribution of forkhead box O3a and its modulation by apigenin, and iv) IKKa/? as a molecular target for the anticancer effects of apigenin in vivo on TRAMP mice. We expect that understanding the molecular mechanisms underlying the anti-cancerous effects of apigenin may be helpful in developing effective chemopreventive/therapeutic strategies based upon targeting these key molecular mechanisms more effectively and with fewer associated side-effects.

Public Health Relevance

Numerous studies have shown that apigenin (4', 5, 7-trihydroxyflavone), a naturally occurring plant flavone abundantly present in common fruits and vegetables, possess promising cancer preventive and therapeutic properties. It has low toxicity, is non-mutagenic, and has shown selective effects in inhibiting cell growth and inducing apoptosis in cancer cells without affecting normal cells. The molecular targets and molecular mechanisms are not fully investigated. We have previously demonstrated that apigenin inhibits multiple signal transduction pathways, specifically the IGF-I axis, PI3K-Akt, NF-(B and ?-Catenin pathways. In this renewal application, we hypothesize that apigenin binds to and inhibit IKKa/?, independent of NF-(B regulation thereby suppressing prostate cancer development and progression. Understanding the molecular mechanisms of apigenin may reveal key molecular targets for the development of more effective agents with fewer side-effects for future use in chemopreventive/therapeutic regimens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108512-08
Application #
8257537
Study Section
Special Emphasis Panel (ZRG1-OTC-B (03))
Program Officer
Perloff, Marjorie
Project Start
2004-09-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$238,800
Indirect Cost
$86,698
Name
Case Western Reserve University
Department
Urology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Shankar, Eswar; Bhaskaran, Natarajan; MacLennan, Gregory T et al. (2015) Inflammatory Signaling Involved in High-Fat Diet Induced Prostate Diseases. J Urol Res 2:
Kanwal, Rajnee; Gupta, Karishma; Gupta, Sanjay (2015) Cancer epigenetics: an introduction. Methods Mol Biol 1238:3-25
Shukla, Sanjeev; Kanwal, Rajnee; Shankar, Eswar et al. (2015) Apigenin blocks IKKα activation and suppresses prostate cancer progression. Oncotarget 6:31216-32
Shukla, Sanjeev; Shankar, Eswar; Fu, Pingfu et al. (2015) Suppression of NF-κB and NF-κB-Regulated Gene Expression by Apigenin through IκBα and IKK Pathway in TRAMP Mice. PLoS One 10:e0138710
Deb, Gauri; Thakur, Vijay S; Limaye, Anil M et al. (2015) Epigenetic induction of tissue inhibitor of matrix metalloproteinase-3 by green tea polyphenols in breast cancer cells. Mol Carcinog 54:485-99

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