Aims: Raloxifene, a selective estrogen receptor (ER) modulator, has been reported to exert the tumor-suppressive effects in both ER-positive and ER-negative cancer cells; however, the mechanisms underlying its ER-independent anti-cancer effects are poorly understood. The NLRP3 inflammasome, a critical component of the innate immune system, has recently received growing attention owing to its multifaceted roles in various aspects of cancer development. The present study aimed at examining the involvement of NLRP3 inflammasomes in the anti-breast cancer effects of raloxifene and its underlying mechanisms. Results: Raloxifene significantly inhibited the activation of NLRP3 inflammasomes in various breast cancer cell lines. Importantly, forced expression of a gain-of-function variant of NLRP3 rescued breast cancer cells from growth arrest by raloxifene, suggesting that the suppression of NLRP3 inflammasomes activation mediates the raloxifene-induced inhibition of breast cancer growth. Mechanistically, raloxifene suppressed NLRP3 inflammasomes activation by lowering the cellular levels of reactive oxygen species (ROS) through the modulation of redox signaling mediated via aryl hydrocarbon receptor (AhR)-nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 (HO-1) axis or the impaired generation of mitochondrial ROS in a mitophagy-dependent manner. Further, the blockage of AhR signaling or inhibition of mitophagy abolished the tumor-suppressive effect of raloxifene in a human breast tumor xenograft model. Innovation: We elucidate a novel molecular mechanism underlying the breast tumor suppressing effect of raloxifene. Conclusion: The results observed in this study suggest that the modulation of NLRP3 inflammasomes activation is a critical event in the inhibition of breast tumor growth by raloxifene. Antioxid. Redox Signal. 37, 1030-1050.
Keywords: aryl hydrocarbon receptor; inflammasomes; mitophagy; raloxifene; redox signaling.