GNETIN C INHIBITS REACTIVATED ANDROGEN RECEPTOR SIGNALLING IN ADVANCED PROSTATE CANCER WITH NEUROENDOCRINE FEATURES

Abstract

ABSTRACT Prostate cancer (PCa) is the second most prevalent cancer in males and the top cause of cancer-related mortality in the United States. After a significant clinical response to androgen deprivation therapy (ADT), patients with advanced PCa frequently relapse with more aggressive castrate-resistant prostate cancer (CRPC), sometimes with neuroendocrine features. Androgen Receptor inhibitor enzalutamide (ENZ) is hormone therapy used to treat men with advanced prostate cancer who have failed other treatments. Accordingly, androgen receptor (AR) reactivation occurs by AR overexpression, mutation, or production of AR splice variants AR-V7, lacking the ligand-binding domain in the AR gene structure, leading to AR-independent and ENZ-resistant cancer cells. Consequently, designing treatments that effectively suppress tumor-promoting AR activity in CRPC is urgently needed. Researchers attempt to treat cancer by developing combination therapy strategies that include a natural substance and a drug already approved by the food and drug administration (FDA). Previously, Dr. Levenson’s lab has shown that stilbene polyphenols can inhibit the expression of AR in LNCaP and 22Rv1 PCa cells. Phytochemical Gnetin C, a resveratrol dimer found in high concentrations in the melinjo plant (Gnetum gnemon), has potent biological characteristics compared to other resveratrol analogs since it has a better pharmacokinetic profile. The current study hypothesized that Gnetin C in combination with ENZ presents effective therapeutic approach in PCa. We found that Gnetin C showed potent blockade of AR signaling by inhibiting both full-length AR and specifically AR-V7 variant in 22Rv1 CRPC cells. Natural bioactive stilbenes have previously exhibited anticancer activity by targeting metastasis-associated protein 1 (MTA1) in Dr. Levenson's lab. Gnetin C also displayed a decrease of MTA1 expression in 22Rv1 cells. We also evaluated neuroendocrine markers; chromogranin A(CHGA) and synaptophysin (SYP) because they have been linked to CRPC. When Gnetin C and ENZ were combined, they had a more inhibitory effect on AR/AR-V7 than resveratrol, pterostilbene, or ENZ, a well-known AR antagonist used in the clinic. In addition, Gnetin C, when combined with ENZ, suppressed neuroendocrine markers (SYP and CHGA) as well as an oncogenic marker, MTA1. In summary, we propose that Gnetin C is the most effective stilbene for inhibiting ARs reactivation in PCa, therefore it may have great potential for chemopreventive and therapeutic implications in the treatment of CRPC.