Adiponectin suppresses inflammasomes activation in breast cancer cells via sestrin-2 induction


Year:

Session type:

Theme:

Duc-Vinh Pham1,Pawan Kumar Raut1,Ananda Baral1,Su-min Lee1,Thi-Hong-Van Tran1,Pil-Hoon Park1
1Yeungnam University

Abstract

Background

Adiponectin, an adipokine derived from adipose tissue, potently inhibits growth of breast cancer cells. However, its mechanisms of action remain to be fully elucidated. There is a growing appreciation that inflammasomes, an intracellular multimeric protein complex playing a key role in inflammation and innate immune, and sestrin-2 (SESN2) are implicated in tumor growth. Here, we demonstrate the modulation of the inflammasome activation through up-regulation of SESN2 expression is a new potential molecular mechanism underlying anti-cancer effects of this adipokine.

Method

Immunoblotting and immunocytochemistry were employed to investigate the effect of adiponectin on the inflammasome signaling. Changes in cell survival and proliferation rate under treatment with adiponectin and pharmacological inhibitors of inflammasomes were monitored by MTS assay, caspase-7 activity measurement and flow cytometry analysis. The molecular mechanisms by which adiponectin inhibits inflammasomes activation were explored using immunoprecipitation in combination with RNA interference and Western blot analysis. 

Results

Globular adiponectin (gAcrp) suppressed the expression levels of the inflammasome components, including NLRP3 and ASC, and inhibited the interleukin-1β (IL-1β) maturation and caspase-1 activation in MCF-7 breast cancer cells. Treatment with gAcrp or pharmacological inhibitors of the inflammasome, including MCC950 (a NLRP3 inhibitor), AC-YVAD-cmk (a caspase-1 inhibitor), IL-1 receptor antagonist, decreased the cancer cell growth via induction of apoptosis and G0/G1 arrest. In addition, gAcrp was found to increase expression level of SESN2 and promote the SESN2-AMPK association which facilitated AMPK phosphorylation. Furthermore, gene silencing of AMPK abrogated the effect of gAcrp on IL-1β maturation and caspase-1 activation, revealing a critical role of SESN2/AMPK axis in the inhibition of inflammasomes by gAcrp.

Conclusion

These findings suggest that adiponectin downregulates the inflammasome signaling that might lead to suppression of breast cancer cell growth and these effects are mediated by SESN2 induction and AMPK phosphorylation.