Honokiol sensitizes breast cancer cells to TNF-α induction of apoptosis by inhibiting Nur77 expression

BACKGROUND AND PURPOSE The orphan nuclear receptor Nur77 is implicated in the survival and apoptosis of cancer cells. The purpose of this study was to determine whether and how Nur77 serves to mediate the effect of the inflammatory cytokine TNF-alpha in cancer cells and to identify and characterize new agents targeting Nur77 for cancer therapy. EXPERIMENTAL APPROACH The effects of TNF- on the expression and function of Nur77 were studied using in vitro and in vivo models. Nur77 expression was evaluated in tumour tissues from breast cancer patients. The anticancer effects of honokiol and its mechanism of action were assessed by in vitro, cell-based and animal studies. KEY RESULTS TNF-alpha rapidly and potently induced the expression of Nur77 in breast cancer cells through activation of IB kinase and JNK. Knocking down Nur77 resulted in TNF-alpha-dependent apoptosis, while ectopic Nur77 expression in MCF-7 cells promoted their growth in animals. Levels of Nur77 were higher in tumour tissues than the corresponding tissues surrounding the tumour in about 50% breast cancer patients studied. Our in vitro and animal studies also identified honokiol as an effective sensitizer of TNF-alpha-induced apoptosis by inhibiting TNF-alpha-induced Nur77 mRNA expression, which could be attributed to its interference of TNFR1's interaction with receptor-interacting protein 1 (RIPK1). CONCLUSIONS AND IMPLICATIONS TNF-alpha-induced Nur77 serves as a survival factor to attenuate the death effect of TNF-alpha in cancer cells. With its proven human safety profile, honokiol represents a promising agent that warrants further clinical development.