期刊
BIOCHEMICAL PHARMACOLOGY
卷 180, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2020.114186
关键词
Adiponectin; Estrogen receptor; Heme oxygenase-1; Inflammasomes; Leptin
资金
- Basic Science Research Program of the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2018R1D1A1B07049701, 2020R1A6A1A03044512]
Accumulating evidence suggests that adipokines, a group of hormones secreted from adipose tissue, modulate tumor growth in a complicated manner. Among diverse adipokines, adiponectin exerts potent anti-tumor activities, whereas leptin exhibits pro-tumorigenic properties. Herein, we have examined the opposing effect of adiponectin on leptin-induced growth of cancer cells and investigated the underlying mechanisms, particularly in the context of inflammasomes activation, which plays a role in the growth of cancer cells. Globular adiponectin (gAcrp) significantly suppressed leptin-induced growth of human breast (MCF-7) and hepatic (HepG2) cancer cells by modulating both cell cycle and apoptosis. To elucidate the underlying mechanisms, we examined the modulatory effects of gAcrp and leptin on inflammasomes. Herein, we showed that gAcrp substantially abolished leptin-induced inflammasomes activation, as evidenced by suppression of IL-1 beta maturation, caspase-1 activation, and downregulation of inflammasomes components, including NLRP3 and ASC, in both MCF-7 and HepG2 cancer cells. Interestingly, suppression of inflammasomes activation by gAcrp was almost completely restored by blockade of heme oxygenase-1 (HO-1) signaling. In addition, suppressive effects of gAcrp on ROS production and NADPH oxidase activation, both of which critically contribute to leptin-induced inflammasomes activation, disappeared by inhibition of HO-1 signaling. Moreover, gAcrp downregulated estrogen receptor-alpha (ER-alpha) expression and blocked leptin-induced ER-alpha activation, which also plays an important role in inflammasomes activation. Finally, the opposing effects of gAcrp on leptin-induced inflammasomes activation and tumor growth were further confirmed in MCF-7 tumor xenografts. In summary, treatment with gAcrp prevents leptin-induced cancer cell growth by modulating inflammasome activation, which is mediated, at least in part, via HO-1 induction and modulation of ER-alpha signaling.
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