STAT3 is constitutively activated in multiple malignant tumors. Compared with regular estrogen receptor (ER)-positive breast cancers, the patients with tamoxifen-resistant breast cancers often exhibit higher levels of STAT3 phosphorylation. Narciclasine (Nar) possesses strong inhibiting effects against a variety of cancer cells; however, the underlying antitumor target(s)/mechanism(s) remains barely understood. In this study, we successfully identified the STAT3 was the direct target of Nar through the combination strategies of connectivity map and drug affinity responsive target stability. In MCF7 cells, Nar could suppress phosphorylation, activation, dimerization, and nuclear translocation of STAT3 by directly binding with the STAT3 SH2 domain. In addition, Nar could specifically degrade total STAT3 via the proteasome pathway in MCF-7/TR (tamoxifen-resistant MCF-7) cells. This distinct mechanism of Nar-targeting STAT3 was mainly attributed to the various levels of reactive oxygen species in regular and tamoxifen-resistant ER-positive breast cancer cells. Meanwhile, Nar-loaded nanoparticles could markedly decrease the protein levels of STAT3 in tumors, resulting in significantly increased MCF-7/TR xenograft tumor regression without obvious toxicity. Our findings successfully highlight the STAT3 as the direct therapeutic target of Nar in ER-positive breast cancer cells, especially, Nar leaded STAT3 degradation as a promising strategy for the tamoxifen-resistant breast cancer treatment.
Keywords: MCF-7/TR; ROS; STAT3; nanoparticles; narciclasine.
© 2022 The Authors.