The interplay between metastasis-associated protein 1 and protein kinase B (MTA1/AKT) signaling has been implicated in driving prostate tumor expansion. Plant-derived polyphenols—especially stilbene compounds—have emerged as promising agents for interrupting MTA1-driven prostate malignancy. In this work, we utilized a prostate-specific transgenic mouse line featuring MTA1 overexpression combined with phosphatase and tensin homolog (Pten) deletion (R26MTA1; Ptenf/f), as well as PC3M prostate cancer cells, both of which model key alterations found in advanced disease. Mechanistic studies revealed that either silencing MTA1 or chemically suppressing it with gnetin C (a resveratrol dimer) in PC3M cells led to substantial suppression of mammalian target of rapamycin (mTOR) activity. In vivo, mice received daily intraperitoneal injections of gnetin C (7 mg/kg bw) for 12 weeks without exhibiting toxicity. Gnetin C treatment significantly curtailed proliferation and angiogenesis while enhancing apoptosis in mice with late-stage prostate tumors. Moreover, beyond lowering MTA1 expression in prostate epithelial cells, gnetin C strongly diminished mTOR signaling in prostate tissues, including the phosphorylation of mTOR-regulated proteins p70 ribosomal S6 kinase (S6K) and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Altogether, these results identify gnetin C as a natural anticancer agent capable of counteracting MTA1/AKT/mTOR-driven prostate cancer, supporting its potential as a standalone therapy or as a complement to approved mTOR inhibitors.
