Pterostilbene Acts through Metastasis-Associated Protein 1 to Inhibit Tumor Growth, Progression and Metastasis in Prostate Cancer

Abstract

The development of natural product agents with targeted strategies holds promise for enhanced anticancer therapy with reduced drug-associated side effects. Resveratrol found in red wine, has anticancer activity in various tumor types. We reported earlier on a new molecular target of resveratrol, 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 resveratrol as a regulator of MTA1/NuRD complex and re-activator of p53 acetylation in prostate cancer (PCa). In the current study, we addressed whether resveratrol analogues also possess the ability to inhibit MTA1 and to reverse p53 deacetylation. We demonstrated that pterostilbene (PTER), found in blueberries, had greater increase in MTA1-mediated p53 acetylation, confirming superior potency over resveratrol as dietary epigenetic agent. In orthotopic PCa xenografts, resveratrol and PTER significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis. Furthermore, MTA1-knockdown sensitized cells to these agents resulting in additional reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling showing increased p53 acetylation, higher apoptotic index and less angiogenesis 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 tested in advanced PCa.

MTA1 drives malignant progression and bone metastasis in prostate cancer

“…Prostate cancer cells, PC3M and LNCaP, were maintained in RPMI 1640 media containing 10% FBS as described previously (Butt et al ., 2017; Dhar et al ., 2016; Dias et al ., 2013a,b; Li et al ., 2013). PC3M cells expressing luciferase (PC3M‐Luc) were established, expanded, and tested for their luciferase activity using an IVIS Spectrum (PerkinElmer, Waltham, MA, USA).…”

“…Western blot analysis was carried out as described previously (Butt et al ., 2017; Dhar et al ., 2015a,b, 2016, 2017; Dias et al ., 2013a,b; Kai et al ., 2010, 2011; Li et al ., 2013). The antibodies used in this study are listed in Table S1.…”

“…For s.c. xenografts, mice were randomly divided into two groups ( n  = 5 per group), and PC3M‐Luc‐NS and PC3M‐Luc shMTA1 cells (0.5 × 10 6 ) in 100 μL of 50% Matrigel (Corning Life Sciences) were inoculated on the dorsal right flank of mice. Bioluminescent and caliper measurements were taken weekly as described previously (Dhar et al ., 2015a,b; Dias et al ., 2013a, b; Kai et al ., 2011; Li et al ., 2013). Calculation of tumor volume by digital vernier caliper measurements was made using formula as before (Dhar et al ., 2015b; Kai et al ., 2011).…”

“…Bioluminescent measurements were taken immediately and then weekly as described previously (Dhar et al ., 2015a,b; Dias et al ., 2013b; Kai et al ., 2011; Li et al ., 2013). The mice were sacrificed at day 34.…”

“…We have extensively reported on the critical role of MTA1 and its signaling at all stages of prostate cancer development and progression (Levenson et al ., 2014). In addition to our initial demonstration of MTA1's functional role in vitro and in xenografts (Dhar et al ., 2015a; Kai et al ., 2010, 2011; Li et al ., 2013), we recently demonstrated that MTA1 overexpression promotes molecular changes associated with inflammation‐mediated cancer initiation, epithelial‐to‐mesenchymal transition (EMT), and cancer progression linked to cell metastatic potential and angiogenesis in a multistage transgenic model of prostate cancer that closely mimics human disease (Butt et al ., 2017; Dhar et al ., 2016, 2017). Altogether, MTA1 is increasingly being recognized as an important upstream multifunctional regulator that affects various cellular responses, including cell adhesion, migration, and invasion in prostate cancer.…”