MTA1-Dependent Anticancer Activity of Gnetin C in Prostate Cancer

Abstract

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.

Dietary stilbenes as modulators of specific miRNAs in prostate cancer

“…The inhibitory effects of resveratrol and pterostilbene on MTA1-mediated angiogenesis involving HIF-1a, VEGF, and IL-1β were also consistently reported (Kai et al, 2011;Li et al, 2013;Dhar et al, 2016;Butt et al, 2017;Hemani et al, 2022). We have also shown the MTA1-mediated and MTA1 independent chemopreventive and therapeutic value of Gnetin C in prostate cancer in vitro and in vivo (Kumar et al, 2019;Gadkari et al, 2020). Importantly, stilbenes can inhibit MTA1-associated oncogenic miRNAs (Figure 3).…”

“…Nutritional interception in intermediate- and high-risk active surveillance patients should target specific molecular pathways. Particularly, our group has shown that natural dietary stilbenes exhibit targeted chemoprotective, interceptive and therapeutic effects against prostate cancer in vitro and in vivo ( Kai et al, 2010 ; Li et al, 2013 ; Dhar et al, 2016 ; Butt et al, 2017 ; Kumar et al, 2019 ; Gadkari et al, 2020 ; Levenson, 2020 ; Hemani et al, 2022 ). This review will focus on the potential of natural stilbenes to protect against prostate cancer through the modulation of specific miRNAs that can conceivably be detected in bloodstream and urine and serve as prognostic and predictive biomarkers for certain populations of prostate cancer patients in the future.…”

“…Moreover, a recent report demonstrated potent anti-angiogenic effect of astringin as well as of resveratrol dimers ε-viniferin, ω-viniferin, and pallidol (C 28 H 22 O 6 ), also concentrated in grapes and red wine ( Fernandez-Cruz et al, 2019 ). Gnetin C (C 28 H 22 O 6 ), a resveratrol dimer found in melinjo ( Gnetum gnemon ) seed extracts that are commonly used in Indonesian cuisine, possesses a broad spectrum of the same pharmacological activities as other stilbenes with the advantage of superior bioavailability and biological efficacy ( Narayanan et al, 2015 ; Kumar et al, 2019 ; Gadkari et al, 2020 ). Chemopreventive effects of dietary stilbenes are mainly due to their anti-inflammatory and antioxidant activity but also direct targeting of multiple signaling pathways involved in carcinogenesis, cancer progression and metastasis.…”

A circadian rhythm-related gene signature for predicting relapse risk and immunotherapeutic effect in prostate adenocarcinoma

“…Here, the present study indicated its role in predicting recurrence risk of prostate cancer. MTA1 has been reported to drive malignant progression and bone metastasis in prostate cancer in several studies [ 33 , 34 ], whereas the protective effect of TP53 is well-known [ 35 , 36 ]. RORC encoding ROR-γ could induce androgen expression in prostate cancer [ 37 ] and is a potential therapeutic target in castration-resistant prostate cancer [ 38 ].…”

Dietary Factors and Prostate Cancer Development, Progression, and Reduction

“…Lundqvist et al [ 213 ] demonstrated, using prostate cancer (LNCaP) and normal prostate (RWPE) epithelial cells, that resveratrol and its analogs inhibited the activation of androgen receptors. Furthermore, Kumar et al [ 214 ] showed in two lines (DU145 and PCM3) of human prostate carcinoma cells that dimer resveratrol gnetin C, which is a natural resveratrol dimer found in melinjo ( Gnetum gnemon L.) seeds [ 215 ], downregulated the metastasis-associated 1 protein (MTA1)-mediated pathway, while promoting the apoptosis and decreasing the aggressiveness of prostate cancer cells. The anti-cancer action mediated by gnetin C turned out to be more potent compared to resveratrol.…”