Wedelolactone, an anti-inflammatory botanical, interrupts c-Myc oncogenic signaling and synergizes with enzalutamide to induce apoptosis in prostate cancer cells

Abstract

The c-Myc gene encodes an oncoprotein transcription factor which is frequently up-regulated in almost all cancer types, and is the subject of intense investigation for management of cancer because of its pleiotropic effects controlling a spectrum of cellular functions. However, due of its non-enzymatic nature, development of suitable strategies to block its protein-protein or protein-DNA interaction is challenging. Thus, c-Myc has been recognized as an elusive molecular target for cancer control and various approaches are in development to inhibit c-Myc-transcriptional activity. We observed that wedelolactone (WDL), an anti-inflammatory botanical compound, severely down-regulates the expression of c-Myc mRNA in prostate cancer cells. Moreover, WDL dramatically decreases the protein level, nuclear localization, DNA-binding, and transcriptional activities of c-Myc. c-Myc is a transforming oncogene widely expressed in prostate cancer cells and is critical for maintaining their transformed phenotype. Interestingly, WDL was found to strongly affect the viability of Myc-activated prostate cancer cells, and completely blocks their invasion as well as soft-agar colony-formation in vitro. WDL was also found to down-regulate c-Myc in vivo in nude mice xenografts. Moreover, WDL synergizes with enzalutamide to decrease the viability of androgen-sensitive prostate cancer cells via induction of apoptosis. These findings reveal a novel anticancer mechanism of the natural compound, WDL, and suggest that the oncogenic function of c-Myc in prostate cancer cells can be effectively down-regulated by WDL for the development of a new therapeutic strategy against Myc-driven prostate cancer.