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Incidence and mortality rates for prostate cancer remain high due to advanced disease characterized by the heterogeneous activation of numerous molecular pathways. In the current study, utilizing a genetic mouse model of advanced prostate cancer with hyperactivated metastasis-associated protein 1/mammalian target of rapamycin (MTA1/mTOR) tumor-promoting pathway, we show for the first time that gnetin C, a natural compound from the melinjo plant, blocks the progression of prostate cancer by reducing cell proliferation and angiogenesis and promoting cell death through the efficient targeting of the MTA1/mTOR pathway. These data may provide a foundation from which to explore gnetin C as a monotherapy and/or combination therapy with approved drugs against advanced prostate cancer in patients with a loss of phosphatase and tensin homolog (PTEN) expression and activated MTA1/mTOR signaling.

The metastasis-associated protein 1/protein kinase B (MTA1/AKT) signaling pathway has been shown to cooperate in promoting prostate tumor growth. Targeted interception strategies by plant-based polyphenols, specifically stilbenes, have shown great promise against MTA1-mediated prostate cancer progression. In this study, we employed a prostate-specific transgenic mouse model with MTA1 overexpression on the background of phosphatase and tensin homolog (Pten) null (R26^MTA1; Pten^f/f) and PC3M prostate cancer cells which recapitulate altered molecular pathways in advanced prostate cancer. Mechanistically, the MTA1 knockdown or pharmacological inhibition of …