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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160867-02
Application #
8278499
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Kim, Young S
Project Start
2011-07-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$308,138
Indirect Cost
$100,638
Name
University of Wisconsin Madison
Department
Dermatology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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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
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
Ahmad, Nihal; Mukhtar, Hasan (2013) Antioxidants meet molecular targets for cancer prevention and therapeutics. Antioxid Redox Signal 19:85-8
Syed, Deeba N; Adhami, Vaqar M; Khan, Mohammad Imran et al. (2013) Inhibition of Akt/mTOR signaling by the dietary flavonoid fisetin. Anticancer Agents Med Chem 13:995-1001
Tarapore, Rohinton S; Siddiqui, Imtiaz A; Mukhtar, Hasan (2012) Modulation of Wnt/?-catenin signaling pathway by bioactive food components. Carcinogenesis 33:483-91