Cancers | Free Full-Text | The Therapeutic Efficacy and Mechanism of Action of Gnetin C, a Natural Compound from the Melinjo Plant, in a Preclinical Mouse Model of Advanced Prostate Cancer

Prostate cancer patients are a heterogeneous group with a prognosis ranging from full recovery to malignant and lethal disease. Between 2007 and 2014, the number of prostate cancers diagnosed declined due to changes in screening recommendations concerning the detection of prostate-specific antigen. Consequently, the incidence rate for advanced stage prostate cancer has increased by about 5% per year [1]. Therefore, an urgent need exists to better understand the biological basis for the progression to aggressive disease and metastasis. Prostate tumors begin from preinvasive lesions such as prostatic intraepithelial neoplasia (PIN), which eventually progress to adenocarcinoma and, in some cases, metastatic disease. Different phases of prostate cancer are characterized by a distinct molecular makeup, during which various signaling pathways are activated. While androgen receptor (AR) signaling is considered the most critical pathway in hormone-sensitive disease, hormone-refractory tumors, which emerge after failing hormone deprivation therapy, are governed by the activation of other tumor-promoting networks, such as the phosphatase and tensin homolog (PTEN) loss of function-associated activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) cell survival signaling pathway [2,3,4,5,6,7]. Yet another pathway having major implications in advanced prostate cancer is metastasis-associated protein 1 (MTA1) signaling, which is strongly associated with clinically aggressive prostate cancer [8,9]. We have previously reported increased levels of MTA1 in Pten-deficient and Pten-loss mouse models of prostate cancer, which affected downstream inflammation and cell survival pathways [10]. Our initial finding that reduced levels of MTA1 were inversely correlated with PTEN acetylation and activation, which resulted in significantly inhibited disease progression partly through the inhibition of p-AKT, revealed a novel deregulated signaling network in prostate cancer: the MTA1/PTEN/AKT pathway [10,11]. Furthermore, our recent studies in a mouse model of premalignant high-risk prostate cancer (R26^MTA; Pten^+/f; Pb-Cre⁺) demonstrated that targeting the MTA1/PTEN/AKT signaling pathway by diets supplemented with natural stilbenes, such as pterostilbene and gnetin C (dimer resveratrol), was effective in preventing prostate cancer progression from high-grade PIN to adenocarcinoma [12,13].

Despite significant advances in developing pharmacological inhibitors of PI3K/AKT/mTOR kinases, the results from clinical trials in prostate cancer demonstrated severe toxicity [14] and a lack of clinical benefit [15]. In the last two decades, there has been much interest in the potential health benefits of plant-based natural polyphenols as anti-inflammatory and anticancer agents [16,17,18]. Different classes of polyphenols have been shown to have anticancer effects through numerous signaling pathways including PI3K/AKT/mTOR [19,20,21]. Our group systematically reported on MTA1-mediated anticancer effects by members of the stilbene family of polyphenols, namely resveratrol, pterostilbene, and gnetin C [10,22]. We recently demonstrated gnetin C as a preclinical tumor growth inhibitor in prostate cancer xenografts and as a dietary interceptive agent in a transgenic mouse model of prostate cancer [13,23]. Based on our previous findings, we hypothesized that gnetin C might be effective as an MTA1-targeted therapeutic agent against advanced prostate cancer. Two major advantages will be gained: (1) new biomarkers such as MTA1 involved in the AKT/mTOR pathway may allow for the selection of a subpopulation of patients more likely to benefit from inhibitors of specific pathways that do not alter kinase activity; (2) safe natural compounds with the ability to inhibit this pathway through MTA1 may provide the rationale for novel combination approaches with low toxicity.