Beta-naphthoflavone (DB06732) mediates estrogen receptor-positive breast cancer cell cycle arrest through AhR-dependent regulation of PI3K/AKT and MAPK/ERK signaling

Abstract

Beta-naphthoflavone (BNF, DB06732) is an agonist of aryl hydrocarbon receptor (AhR) and a putative chemotherapeutic agent that has antitumor activity against mammary carcinomas in vivo. However, the mechanism by which BNF exerts this antitumor effect remains unclear. Thus, we explored mechanisms of BNF's antitumor effects in human breast cancer cells. This study showed that BNF suppressed cell proliferation and induced cell cycle arrest in the G0/G1 phase with downregulation of cyclin D1/D3 and CDK4 and upregulation of p21(Cip1/Waf1), leading to a senescence-like phenotype in estrogen receptor (ER)-positive MCF-7 cells, but not in ER-negative MDA-MB-231 cells. In addition, BNF inhibited PI3K/AKT signaling, and the PI3K inhibitor, LY294,002, exhibited the same inhibitory effects on cyclinD1/D3, CDK4 and the cell cycle as BNF. Interestingly, BNF activated mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) signaling, and more notably, MEK inhibitor PD98059 significantly blocked the BNF-induced cell cycle arrest and upregulation of p21(Cip1/Waf1). Furthermore, specific ERα and AhR siRNA studies indicate that ERα is required in BNF-induced p21(Cip1/Waf1) expression, and BNF-mediated cell cycle arrest and modulation of AKT and ERK signaling is AhR-dependent. Taken together, AhR-dependent inhibition of the PI3K/AKT pathway, activation of MAPK/ERK and modulation of ERα is a novel mechanism underlying BNF-mediated antitumor effects in breast cancer, which may represent a promising strategy to be exploited in future clinical trials.

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

“…The MCF‐7 cells were found to arrest at the G 0 /G 1 phase, resulting in cell senescence. This inhibition of proliferation was not observed in the MDA‐MB‐231 cells and was shown to be AhR dependent …”

“…αNF has also been found to be a weak AhR agonist, though only at high concentrations . Known to be a strong inducer of CYP1A1, βNF displays antitumor activity against ER‐positive (MCF‐7), but not ER‐negative (MDA‐MB‐231), oncogenic breast cell lines in vivo . The MCF‐7 cells were found to arrest at the G 0 /G 1 phase, resulting in cell senescence.…”

Effect of Natural Polyphenols on CYP Metabolism: Implications for Diseases

“…174 This property of β-NF mediates its antitumor activity in breast cancer. 175 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 33 leading the cells to apoptosis. The treatment of the cells with the AhR antagonist α-NF prior to the exposure to AF resulted in the decrease of apoptosis indicating that the antiproliferative effect of AF is mediated by the stimulation of AhR.…”

AhR ligand aminoflavone suppresses α6‐integrin–Src–Akt signaling to attenuate tamoxifen resistance in breast cancer cells

“…AhR agonist with in vivo antitumor activity, was found to inhibit PI3K-Akt signaling in MCF-7 cells in an AhR-dependent manner (Wang, Xu, Bu, Bottum, & Tischkau, 2014). On the other hand, GoH3 specifically blocks the function of α6-integrin and thus AF and GoH3…”