Dietary Pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer

Authors: DHAR, SWATI - University Of Mississippi Medical Center; KUMAR, AVINASH - University Of Mississippi Medical Center; ZHANG, LIANGFEN - University Of Mississippi Medical Center; Rimando, Agnes; LAGE, JANICE - University Of Mississippi Medical Center; LEWIN, JACK - University Of Mississippi Medical Center; ATFI, AZEDDINE - University Of Mississippi Medical Center; ZHANG, XU - University Of Mississippi Medical Center; LEVENSON, ANAIT - University Of Mississippi Medical Center

Submitted to: Oncotarget
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/29/2016
Publication Date: 3/1/2016
Publication URL: http://handle.nal.usda.gov/10113/62332
Citation: Dhar, S., Kumar, A., Zhang, L., Rimando, A.M., Lage, J.M., Lewin, J.R., Atfi, A., Zhang, X., Levenson, A.S. 2016. Dietary Pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer. Oncotarget. doi: 10.18632/oncotarget.7841.

Interpretive Summary: Overexpression of the protein metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine whether pterostilbene, a phenolic compound found in some fruits, may effectively target MTA1 to prevent prostate cancer development and progression, and to determine MTA1-driven mechanisms in transgenic mice. We show that high levels of MTA1 expression in mice prostate cooperate with keycancer genes to promote prostate cancer progression. In addition, studies using human prostate cancer cells indicated a direct involvement of MTA1 in inducing inflammation and epithelial-to-mesenchymal transition. Importantly, inhibition of MTA1 by pterostilbene resulted in decreased proliferation and increased cell death. Taken together, our pre-clinical findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression. Our study also provides proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer.

Technical Abstract: Dietary nutrients with ability to reverse adverse epigenetic events have great potential for cancer chemoprevention. 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-driven mechanisms in pre-clinical models of prostate cancer and whether pterostilbene, a natural potent analog of resveratrol, may effectively target MTA1 to prevent prostate cancer development and progression. 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. In addition, 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, thereby restraining prostatic intraepithelial neoplasia (PIN) formation in prostate-specific Pten heterozygous mice by 50% and reducing tumor development and progression in prostate specific Pten-null mice by 52%. Taken together, our pre-clinical findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression and offer pre-clinical proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer.