Growth of breast cancer cells by leptin is mediated via activation of the inflammasome: Critical roles of estrogen receptor signaling and reactive oxygen species production.

Abstract

Leptin, a hormone primarily derived from adipose tissue, is known to induce tumor growth, but its underlying mechanisms of action are not clearly understood. Inflammasomes, acting as signaling platforms for controlling inflammatory responses, modulate tumor growth in a complicated manner. In this study, we investigated the role of inflammasomes in leptin-induced growth of breast cancer cells. Herein, we showed that leptin activated NLRP3 inflammasomes in MCF-7 breast cancer cells, as determined by activation of caspase-1, maturation of interleukin-1β, and increased expression of the inflammasome components, including NLRP3 and ASC. Interestingly, inhibition of the inflammasome by treatment with a pharmacological inhibitor of caspase-1 or gene silencing of NLRP3 prevented leptin-induced increase in cell viability. Moreover, suppression of apoptosis and cell cycle promotion by leptin were also significantly abolished by gene silencing of NLRP3, clearly indicating a crucial role of NLRP3 inflammasomes in leptin-induced breast cancer growth. In addition, inhibition of estrogen receptor signaling or ROS production markedly blocked leptin-induced activation of NLRP3 inflammasomes, suggesting that estrogen receptor signaling and ROS production mediate inflammasomes activation by leptin. The stimulatory effect of leptin on inflammasomes activation was also observed in MCF-7 tumor xenograft model. Furthermore, the critical roles of inflammasomes activation in leptin-induced tumor growth, suppression of apoptotic gene expression, and induction of the genes stimulating cell cycle were confirmed in a tumor xenograft model. Taken together, these results demonstrate that inflammasomes activation plays a pivotal role in leptin-induced growth of breast cancer cells via modulation of both apoptosis and cell cycle.

• Authors: Pawan Kumar Raut, Sang-Hyun Kim, Dong Young Choi, Gil-Saeng Jeong, Pil-Hoon Park
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 161 Pg. 73-88 (03 2019) ISSN: 1873-2968 [Electronic] England
• PMID: 30633869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Leptin
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Reactive Oxygen Species
• Receptors, Estrogen

Topics

• Animals
• Breast Neoplasms (metabolism, pathology)
• Cell Proliferation (drug effects, physiology)
• Cell Survival (drug effects, physiology)
• Female
• Humans
• Leptin (metabolism, pharmacology)
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Reactive Oxygen Species (metabolism)
• Receptors, Estrogen (physiology)
• Signal Transduction (drug effects, physiology)
• Xenograft Model Antitumor Assays (methods)