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Mol Ther. 2018 Sep 5;26(9):2255-2266. doi: 10.1016/j.ymthe.2018.06.016. Epub 2018 Jun 22.

Combination of Asiatic Acid and Naringenin Modulates NK Cell Anti-cancer Immunity by Rebalancing Smad3/Smad7 Signaling.

Author information

1
Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
2
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
3
Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: hylan@cuhk.edu.hk.

Abstract

Transforming growth factor β1 (TGF-β1) plays a promoting role in tumor growth via a mechanism associated with hyperactive Smad3 and suppressed Smad7 signaling in the tumor microenvironment. We report that retrieving the balance between Smad3 and Smad7 signaling with asiatic acid (AA, a Smad7 inducer) and naringenin (NG, a Smad3 inhibitor) effectively inhibited tumor progression in mouse models of invasive melanoma (B16F10) and lung carcinoma (LLC) by promoting natural killer (NK) cell development and cytotoxicity against cancer. Mechanistically, we found that Smad3 physically bound Id2 and IRF2 to suppress NK cell production and NK cell-mediated cytotoxicity against cancer. Treatment with AA and NG greatly inhibited Smad3 translation and phosphorylation while it restored Smad7 expression, and, therefore, it largely promoted NK cell differentiation, maturation, and cytotoxicity against cancer via Id2/IRF2-associated mechanisms. In contrast, silencing Id2 or IRF2 blunted the protective effects of AA and NG on NK cell-dependent anti-cancer activities. Thus, treatment with AA and NG produced an additive effect on inactivating TGF-β1/Smad3 signaling, and, therefore, it suppressed melanoma and lung carcinoma growth by promoting NK cell immunity against cancer via a mechanism associated with Id2 and IRF2.

KEYWORDS:

NK cell immunity; anti-cancer immunotherapy; rebalancing Smad3/Smad7 signaling

PMID:
30017880
PMCID:
PMC6127879
[Available on 2019-09-05]
DOI:
10.1016/j.ymthe.2018.06.016

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