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

Abstract

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.

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.…”

“…qRT‐PCR was performed as described previously (Butt et al ., 2017; Dhar et al ., 2015a,b, 2016, 2017) on the LightCycler 480 II real‐time PCR instrument (Roche Diagnostics, Basel, Switzerland). All primers for qRT‐PCR are listed in Table S2.…”

“…ChIP‐Seq was performed using MTA1 antibody (Bethyl Laboratories, Montgomery, TX, USA) at Active Motif (San Diego, CA, USA). Reads were aligned to the mouse genome, and peaks were identified (Dhar et al ., 2016, 2017) using SICER algorithm. The ChIP‐Seq tracks presented here were generated using the UCSC Genome Browser.…”

“…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.…”