Dietary pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer
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Swati Dhar1,*, Avinash Kumar1,*, Liangfen Zhang1,2, Agnes M. Rimando3, Janice M. Lage2, Jack R. Lewin2, Azeddine Atfi1,4, Xu Zhang5, Anait S. Levenson1,2,6
1Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
2Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA
3United States Department of Agriculture, Agriculture Research Service, Natural Product Utilization Research Unit, University, MS, USA
4Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA
5Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS, USA
6Current affiliation: Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA
*These authors contributed equally to this work
Keywords: pterostilbene, prostate cancer, chemoprevention, therapy, MTA1
Received: October 09, 2015 Accepted: January 29, 2016 Published: March 01, 2016
Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1- targeted chemopreventive and therapeutic efficacy of pterostilbene, a natural potent analog of resveratrol, in pre-clinical models of prostate cancer. Here, we show that high levels of MTA1 expression in Pten-loss prostate cooperate with key oncogenes, including c-Myc and Akt among others, to promote prostate cancer progression. Loss-of-function studies using human prostate cancer cells indicated direct involvement of MTA1 in inducing inflammation and epithelial-to-mesenchymal transition. Importantly, pharmacological inhibition of MTA1 by pterostilbene resulted in decreased proliferation and angiogenesis and increased apoptosis. This restrained prostatic intraepithelial neoplasia (PIN) formation in prostate-specific Pten heterozygous mice and reduced tumor development and progression in prostate-specific Pten-null mice. Our findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression. More significantly, it offers pre-clinical proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer.
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