Prostate cancer often metastasizes to the bone, leading to morbidity and mortality. While metastasis‐associated protein 1 (MTA1) is highly overexpressed in metastatic tumors and bone metastatic lesions, its exact role in the development of metastasis is unknown. Here, we report the role of MTA1 in prostate cancer progression and bone metastasis in vitro and in vivo. We found that MTA1 silencing diminished formation of bone metastases and impaired tumor growth in intracardiac and subcutaneous prostate cancer xenografts, respectively. This was attributed to reduced colony formation, invasion, and migration capabilities of MTA1 knockdown cells. Mechanistic studies revealed that MTA1 silencing led to a significant decrease in the expression of cathepsin B (CTSB), a cysteine protease critical for bone metastasis, with an expected increase in the levels of E‐cadherin in both cells and xenograft tumors. Moreover, meta‐analysis of clinical samples indicated a positive correlation between MTA1 and CTSB. Together, these results demonstrate the critical role of MTA1 as an upstream regulator of CTSB‐mediated events associated with cell invasiveness and raise the possibility that targeting MTA1/CTSB signaling in the tumor may prevent the development of bone metastasis in prostate cancer.

Prostate cancer (PCa), the second leading cause of cancer-related mortality among men in the United States, is marked by profound metabolic reprogramming, particularly in lipid metabolism. This review highlights the pivotal role of altered lipid metabolic pathways, including de novo fatty acid synthesis, fatty acid uptake and transport, β-oxidation, and cholesterol metabolism, in the development, progression, and therapeutic resistance of PCa. Key enzymes and transcription factors, such as FASN, ACLY, SREBPs, and FABPs, which are mainly regulated by androgen receptor signaling, orchestrate a lipogenic phenotype that supports prostate tumor growth and survival. Crosstalk between lipid metabolism and the tumor microenvironment further promotes immune evasion and metastasis. The review also explores therapeutic opportunities in targeting lipid metabolic pathways, highlighting the preclinical and clinical advances in inhibiting FASN, SREBP1, SREBP2, HMGCR, and FABPs, as well as combinatorial strategies with conventional therapies. Understanding the impact of lipid metabolism on PCa pathogenesis provides a promising avenue for developing novel targeted and combinatorial interventions to improve clinical outcomes in PCa.

A key objective of this study was to explore the potential of dietary grape consumption to modulate adverse effects caused by a high-fat (western-pattern) diet. Female C57BL/6J mice were purchased at six-weeks-of-age and placed on a standard (semi-synthetic) diet (STD). At 11 weeks-of-age, the mice were continued on the STD or placed on the STD supplemented with 5% standardized grape powder (STD5GP), a high-fat diet (HFD), or an HFD supplemented with 5% standardized grape powder (HFD5GP). After being provided with the respective diets for 13 additional weeks, the mice were euthanized, and liver was collected for biomarker analysis, determination of genetic expression (RNA-Seq), and histopathological examination. All four dietary groups demonstrated unique genetic expression patterns. Using pathway analysis tools (GO, KEGG and Reactome), relative to the STD group, differentially expressed genes of the STD5GP group were significantly enriched in RNA, mitochondria, and protein translation related pathways, as well as drug metabolism, glutathione, detoxification, and oxidative stress associated pathways. The expression of Gstp1 was confirmed to be upregulated by about five-fold (RT-qPCR), and, based on RNA-Seq data, the expression of additional genes associated with the reduction of oxidative stress and detoxification (Gpx4 and 8, Gss, Gpx7, Sod1) were enhanced by dietary grape supplementation. Cluster analysis of genetic expression patterns revealed the greatest divergence between the HFD5GP and HFD groups. In the HFD5GP group, relative to the HFD group, 14 genes responsible for the metabolism, transportation, hydrolysis, and sequestration of fatty acids were upregulated. Conversely, genes responsible for lipid content and cholesterol synthesis (Plin4, Acaa1b, Slc27a1) were downregulated. The two top classifications emerging as enriched in the HFD5GP group vs. the HFD group (KEGG pathway analysis) were Alzheimer’s disease and nonalcoholic fatty liver disease (NAFLD), both of which have been reported in the literature to bear a causal relationship. In the current study, nonalcoholic steatohepatitis was indicated by histological observations that revealed archetype markers of fatty liver induced by the HFD. The adverse response was diminished by grape intervention. In addition to these studies, life-long survival was assessed with C57BL/6J mice. C57BL/6J mice were received at four-weeks-of-age and placed on the STD. At 14-weeks-of-age, the mice were divided into two groups (100 per group) and provided with the HFD or the HFD5GP. Relative to the HFD group, the survival time of the HFD5GP group was enhanced (log-rank test, p = 0.036). The respective hazard ratios were 0.715 (HFD5GP) and 1.397 (HFD). Greater body weight positively correlated with longevity; the highest body weight of the HFD5GP group was attained later in life than the HFD group (p = 0.141). These results suggest the potential of dietary grapes to modulate hepatic gene expression, prevent oxidative damage, induce fatty acid metabolism, ameliorate NAFLD, and increase longevity when co-administered with a high-fat diet.

Natural stilbenes have gained significant attention in the scientific community owing to their potential anticancer effects against prostate cancer. We recently reported that Gnetin C, a resveratrol (Res) dimer, demonstrated more potent inhibition of metastasis-associated protein 1/v-ets avian erythroblastosis virus E26 oncogene homolog 2 (MTA1/ETS2) axis in prostate cancer cell lines than other stilbenes. In this study, we investigated in vivo antitumor effects of Gnetin C in two doses (50 and 25 mg/kg, i.p.) using PC3M-Luc subcutaneous xenografts and compared these to Res and pterostilbene (Pter). We found that while vehicle-treated mice revealed rapid tumor progression, compounds-treated mice showed noticeable delay in tumor growth. Gnetin C in 50 mg/kg dose demonstrated the most potent tumor inhibitory effects. Gnetin C in 25 mg/kg dose exhibited tumor inhibitory effects comparable with Pter in 50 mg/kg dose. Consistent with the effective antitumor effects, Gnetin C-treated tumors showed reduced mitotic activity and angiogenesis and a significant increase in apoptosis compared to all the other groups. The data suggest that Gnetin C is more potent in slowing tumor progression in prostate cancer xenografts than Res or Pter. Taken together, we demonstrated, for the first time, that Gnetin C is a lead compound among stilbenes for effectively blocking prostate cancer progression in vivo.

The overexpression of metastasis-associated protein 1 (MTA1) in prostate cancer (PCa) contributes to tumor aggressiveness and metastasis. We have reported the inhibition of MTA1 by resveratrol and its potent analog pterostilbene in vitro and in vivo. We have demonstrated that pterostilbene treatment blocks the progression of prostatic intraepithelial neoplasia and adenocarcinoma in mouse models by inhibiting MTA1 expression and signaling. In the current study, we investigated the MTA1 targeted anticancer effects of Gnetin C, a resveratrol dimer, in comparison with resveratrol and pterostilbene. Using DU145 and PC3M PCa cells, we found that Gnetin C downregulates MTA1 more potently than resveratrol and pterostilbene. Further, Gnetin C demonstrated significant MTA1-mediated inhibitory effect on cell viability, colony formation, and migration, while showing a more potent induction of cell death than resveratrol or pterostilbene. In addition, we identified Gnetin C-induced substantial ETS2 (erythroblastosis E26 transformation-specific 2) downregulation, which is not only MTA1-dependent, but is also independent of MTA1 as a possible mechanism for the superior anticancer efficacy of Gnetin C in PCa. Together, these findings underscore the importance of novel potent resveratrol dimer, Gnetin C, as a clinically promising agent for the future development of chemopreventive and possibly combinatorial therapeutic approaches in PCa.

Although the link between diet and cancer is complex, epidemiological data confirm that diet is a risk factor for prostate cancer and indicate a reduced prostate cancer incidence associated with a diet rich in vegetables and fruits. Because of the known protective effect of grape seed extract (GSE) against prostate cancer, we evaluated the effects of grape powder extract (GPE) on cell viability, proliferation, and metastatic capability. Importantly, we explored the possible novel mechanism of GPE through metastasis-associated protein 1 (MTA1) downregulation in prostate cancer, since our previous studies indicated resveratrol (Res)- and pterostilbene (Pter)-induced MTA1-mediated anticancer activities in prostate cancer. We found that GPE inhibited the cell viability and growth of prostate cancer cells only at high 100 μg/mL concentrations. However, at low 1.5–15 μg/mL concentrations, GPE significantly reduced the colony formation and wound healing capabilities of both DU145 and PC3M cells. Moreover, we found that GPE inhibited MTA1 in a dose-dependent manner in these cells, albeit with considerably less potency than Res and Pter. These results indicate that stilbenes such as Res and Pter specifically and potently inhibit MTA1 and MTA1-associated proteins compared to GPE, which contains low concentrations of Res and mainly consists of other flavonoids and anthocyanidins. Our findings support continued interest in GPE as a chemopreventive and anti-cancer agent against prostate cancer but also emphasize the unique and specific properties of stilbenes on MTA1-mediated anticancer effects on prostate cancer.