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.
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.
|Kanwal, Rajnee; Datt, Manish; Liu, Xiaoqi et al. (2016) Dietary Flavones as Dual Inhibitors of DNA Methyltransferases and Histone Methyltransferases. PLoS One 11:e0162956|
|Babcook, Melissa A; Joshi, Aditya; Montellano, Jeniece A et al. (2016) Statin Use in Prostate Cancer: An Update. Nutr Metab Insights 9:43-50|
|Singh, Savita; Zheng, Yun; Jagadeeswaran, Guru et al. (2016) Deep sequencing of small RNA libraries from human prostate epithelial and stromal cells reveal distinct pattern of microRNAs primarily predicted to target growth factors. Cancer Lett 371:262-73|
|Shankar, Eswar; Kanwal, Rajnee; Candamo, Mario et al. (2016) Dietary phytochemicals as epigenetic modifiers in cancer: Promise and challenges. Semin Cancer Biol 40-41:82-99|
|Singh, Savita; Shukla, Girish C; Gupta, Sanjay (2015) MicroRNA Regulating Glutathione S-Transferase P1 in Prostate Cancer. Curr Pharmacol Rep 1:79-88|
|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 IKKÎ± activation and suppresses prostate cancer progression. Oncotarget 6:31216-32|
|Shukla, Sanjeev; Shankar, Eswar; Fu, Pingfu et al. (2015) Suppression of NF-ÎºB and NF-ÎºB-Regulated Gene Expression by Apigenin through IÎºBÎ± 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|
Showing the most recent 10 out of 51 publications