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Title: Pterostilbene acts through metastasis-associated protein 1 to inhibit tumor progression and metastasis in prostate cancer

Author
item KUN, LI - University Of Mississippi Medical Center
item DIAS, STEVEN - University Of Mississippi Medical Center
item Rimando, Agnes
item DHAR, SWATI - University Of Mississippi Medical Center
item Mizuno, Cassia
item PENMAN, ALAN - University Of Mississippi Medical Center
item LEWIN, JACK - University Of Mississippi Medical Center
item LEVENSON, ANAIT - University Of Mississippi Medical Center

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/25/2013
Publication Date: 3/1/2013
Citation: Kun, L., Dias, S.J., Rimando, A.M., Dhar, S., Mizuno, C.S., Penman, A.D., Lewin, J.R., Levenson, A.S. 2013. Pterostilbene acts through metastasis-associated protein 1 to inhibit tumor progression and metastasis in prostate cancer. PLoS One. 8(3):e557542.

Interpretive Summary: We reported earlier on a new molecular target of resveratrol, a phenolic compound found in grapes and wine, the metastasis-associated protein 1 (MTA1). MTA1 is a part of a protein complex that mediates modifications of critical regulators of progression and spread of prostate cancer. MTA1 overexpression correlates with clinical parameters that characterize tumor aggressiveness. In the current study, we addressed whether resveratrol analogues also possess the ability to inhibit MTA1. We found pterostilbene, a component of blueberries, most potently inhibited MTA1 among the analogues in vitro, and showed greater potency over resveratrol. We then examined the MTA1-mediated effects of resveratrol and pterostilbene in clinically relevant animal model. Resveratrol and pterostilbene significantly inhibited tumor progression, local invasion and spontaneous metastasis in MTA1-positive mice at the same degree as in mice injected with MTA1-negative prostate cancer cells. Moreover, absence of MTA1 sensitized cells to resveratrol and pterostilbene resulting in further reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling, based on 3 parameters analyzed, and particularly better responses were observed in pterostilbene- compared to resveratrol-fed mice. Altogether, our results indicate MTA1 as a major contributor in prostate tumor malignant progression, and support the use of strategies targeting MTA1. Our strong pre-clinical data indicate pterostilbene as a potent, selective and pharmacologically safe natural product that may be used in clinic for advanced prostate cancer.

Technical Abstract: The development of natural product agents with targeted strategies holds promise for enhanced anticancer therapy with reduced drug-associated side effects. Resveratrol (Res), found in red wine, has anticancer activity in various tumor types. We reported earlier on a new molecular target of Res, the metastasis-associated protein 1 (MTA1), which is a part of nucleosome remodeling and deacetylation (NuRD) co-repressor complex that mediates gene silencing. We identified Res as a regulator of MTA1/NuRD complex and re-activator of p53 acetylation in prostate cancer (PCa). In the current study, we addressed whether Res analogues also possess the ability to inhibit MTA1 and reverse deacetylation of p53. We found that pterostilbene (PTER), a component of blueberries, most potently inhibits MTA1 in vitro. Importantly, we showed that PTER demonstrated greater increase in MTA1-mediated p53 acetylation, confirming superior potency over Res as dietary epigenetic agent that controls posttranslational modifications of proteins. We then examined the MTA1-mediated effects of Res and PTER in clinically relevant orthotopic PCa xenografts. Resveratrol and PTER significantly inhibited tumor progression, local invasion and spontaneous metastasis in MTA1-positive mice at the same degree as MTA1-knockdown xenografts. Furthermore, MTA1-knockdown sensitized cells to Res and PTER resulting in supplementary reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling showing increased p53 acetylation, higher apoptotic index and less angiogenicity in vivo in all xenografts treated with the compounds, and particularly with PTER. Altogether, our results indicate MTA1 as a major contributor in prostate tumor malignant progression, and support the use of strategies targeting MTA1. Our strong pre-clinical data indicate PTER as a potent, selective and pharmacologically safe natural product that may be used in clinic for advanced PCa.