Prostate cancer is the most commonly diagnosed cancer and the second most common cause of cancer related deaths among men in the US. Although advances in prevention and treatment have improved overall survival, there remains a clear need for effective mechanism-based approaches that can achieve long-term improvements in the management prostate cancer. Among the many signaling networks that have been implicated in the development of prostate cancer are the PTEN/AKT/mammalian target of rapamycin (AKT/mTOR) and MAPK pathways. Notably, the PTEN/AKT/mTOR and MAPK signaling pathways function cooperatively to promote tumor growth and the emergence of hormone-refractory disease. These observations form the basis of our proposal that simultaneous targeting of the PTEN/Akt/mTOR and the MAPK signaling pathways may be an effective strategy for inhibiting the development of prostatic intraepithelial neoplasia (PIN) and its conversion to cancer. In line with this hypothesis and in our pursuit for non-toxic dietary agents for chemoprevention, we recently made some novel and exciting observations with fisetin, a structurally distinct chemical substance that belongs to the flavonoid group of polyphenols. Treatment of prostate cancer PC3 cells with fisetin resulted in inhibition of mTOR kinase signaling. Using a unique family of human prostate epithelial cell lines that mimic multiple steps in the process of prostate carcinogenesis we observed that transformed cells with increased potential for tumorigenesis exhibit higher mTOR signaling and greater sensitivity to fisetin induced cell death. More interestingly, using molecular modeling we observed that fisetin physically interacts with the mTOR molecule and docks at two sites with a binding energy of -8Kcal/mol. These observations provide evidence that fisetin functions as a novel inhibitor of mTOR signaling complex leading to induction of cell death. In this application we propose to take advantage of fisetin's ability to target multiple signaling pathways and investigate its efficacy in vitro using a unique family of six human prostate epithelial cells and in vivo using a genetically engineered Nkx3.1/Pten mutant mouse model that recapitulates many features of human prostate cancer. Most relevant for the current study, Nkx3.1/Pten mutant mice display activation of AKT/mTOR and MAPK signaling during cancer progression. Therefore, we reasoned that these Nkx3.1/Pten mice should provide an excellent preclinical model to test the consequences of simultaneous targeting of AKT/mTOR and ERK MAPK signaling for prostate tumorigenesis. In this application we will 1) establish the involvement of PTEN/Akt/mTOR and the MAPK signaling pathways and determine the efficacy of fisetin in a unique family of human prostate epithelial cell lines that mimic multiple steps in the process of prostate carcinogenesis, 2) investigate the effects of dietary fisetin and involvement of PTEN/Akt/mTOR and the MAPK signaling pathways during the development of PIN and androgen dependent adenocarcinoma in the Nkx3.1/Pten mouse model of prostate cancer and 3) investigate the efficacy of fisetin against castration induced androgen independent adenocarcinoma in the Nkx3.1/Pten mutant mouse model of advanced prostate cancer. A successful completion of this proposal may result in the development of fisetin as a novel agent for prevention and possibly for the treatment of prostate cancer.

Public Health Relevance

Among the major signaling networks that have been implicated in advanced prostate cancer are the AKT/mammalian target of rapamycin (AKT/mTOR) and MAPK pathways. Combinatorial inhibition of the AKT/mTOR and ERK MAPK signaling pathways is highly effective for inhibition of prostate tumorigenicity. Our studies will provide information on the use of a non-toxic dietary ingredient fisetin which inhibits these signaling pathways for the prevention and possible treatment of prostate cancer in an adjuvant setting.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Chemo/Dietary Prevention Study Section (CDP)
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Lin, Alison J
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University of Wisconsin Madison
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Mukhtar, Eiman; Adhami, Vaqar Mustafa; Siddiqui, Imtiaz Ahmad et al. (2016) Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells. Mol Cancer Ther 15:2863-2874
Syed, Deeba N; Adhami, Vaqar Mustafa; Khan, Naghma et al. (2016) Exploring the molecular targets of dietary flavonoid fisetin in cancer. Semin Cancer Biol 40-41:130-140
Khan, Mohammad Imran; Hamid, Abid; Adhami, Vaqar Mustafa et al. (2015) Role of epithelial mesenchymal transition in prostate tumorigenesis. Curr Pharm Des 21:1240-8
Lall, Rahul K; Syed, Deeba N; Adhami, Vaqar M et al. (2015) Dietary polyphenols in prevention and treatment of prostate cancer. Int J Mol Sci 16:3350-76
Shabbir, Maria; Syed, Deeba N; Lall, Rahul K et al. (2015) Potent anti-proliferative, pro-apoptotic activity of the Maytenus royleanus extract against prostate cancer cells: evidence in in-vitro and in-vivo models. PLoS One 10:e0119859
Mukhtar, Eiman; Adhami, Vaqar Mustafa; Sechi, Mario et al. (2015) Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells. Cancer Lett 367:173-83
Mukhtar, Eiman; Adhami, Vaqar Mustafa; Mukhtar, Hasan (2014) Targeting microtubules by natural agents for cancer therapy. Mol Cancer Ther 13:275-84
Syed, Deeba N; Chamcheu, Jean-Christopher; Khan, Mohammad Imran et al. (2014) Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. Biochem Pharmacol 89:349-60
Khan, Mohammad Imran; Adhami, Vaqar Mustafa; Lall, Rahul Kumar et al. (2014) YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin. Oncotarget 5:2462-74
Syed, Deeba N; Lall, Rahul K; Chamcheu, Jean Christopher et al. (2014) Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma. Arch Biochem Biophys 563:108-17

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