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Adiponectin, an adipokine predominantly derived from adipose tissue, exhibits potent antitumor properties in breast cancer cells. However, its mechanisms of action remain elusive. Inflammasomes—intracellular multimeric protein complexes—modulate cancer cell growth in a complicated manner, as well as playing a role in the innate immune system. Herein, we examined the potential role of inflammasomes in the antitumor activity of adiponectin and found that globular adiponectin (gAcrp) significantly suppressed inflammasomes activation in breast cancer cells both in vitro and in vivo conditions, as determined by decreased expression of inflammasomes components, including NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and the apoptosis-associated speck-like protein containing a CARD (ASC), and inhibition of interleukin-1β and caspase-1 activation. Treatment with pharmacological inhibitors of inflammasomes caused decrease in cell viability, apoptosis induction, and G0/G1 cell cycle arrest, suggesting that inflammasomes activation is implicated in the growth of breast cancer cells. In addition, treatment with gAcrp generated essentially similar results to those of inflammasomes inhibitors, further indicating that suppression of breast cancer cell growth by gAcrp is mediated via modulation of inflammasomes. Mechanistically, gAcrp suppressed inflammasomes activation through sestrin2 (SESN2) induction, liver kinase B1 (LKB-1)-dependent AMP-activated protein kinase (AMPK) phosphorylation, and alleviation of endoplasmic reticulum (ER) stress. Taken together, these results demonstrate that gAcrp inhibits growth of breast cancer cells by suppressing inflammasomes activation, at least in part, via SESN2 induction and AMPK activation-dependent mechanisms.

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Leptin, a hormone derived from adipose tissue, promotes growth of cancer cells via multiple mechanisms. Estrogen receptor signaling is also known to stimulate the growth of breast cancer cells. However, the involvement of estrogen receptor signaling in the oncogenic actions of leptin and its underlying mechanisms are not clearly understood. Herein, we investigated mechanisms for estrogen receptor signaling-mediated growth of breast cancer cells, particularly focusing on autophagy, which plays a crucial role in leptin-induced tumor growth. Inhibition of estrogen receptor signaling via gene silencing or treatment with a pharmacological inhibitor (tamoxifen) abolished leptin-induced growth of MCF-7 human breast cancer cells. Interestingly, leptin-induced autophagy activation, determined by up-regulation of autophagy-related genes and autophagosome formation, was also significantly suppressed by inhibiting estrogen receptor signaling. Moreover, inhibition of estrogen receptor markedly prevented leptin-induced activation of AMPK/FoxO3A axis, which plays a crucial role in autophagy induction. Leptin-induced cell cycle progression and Bax down-regulation were also prevented by treatment with tamoxifen. The pivotal roles of estrogen receptor signaling in leptin-induced cell cycle progression, apoptosis suppression, and autophagy induction were further confirmed in MCF-7 tumor xenograft model. Taken together, these results demonstrate that estrogen receptor signaling plays a key role in leptin-induced growth of breast cancer cells via autophagy activation.

No abstract