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

Molecular Therapy : the Journal of the American Society of Gene Therapy
Guang-Yu LianHui-Yao Lan

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 ce...Continue Reading

Citations

Jul 18, 2020·Journal of Leukocyte Biology·Li-Juan DengJia-Xu Chen
Dec 12, 2019·Anti-cancer Agents in Medicinal Chemistry·Muhammad T IslamMohammad S Mubarak
May 19, 2019·International Journal of Molecular Sciences·Hee-Sung ChaeHyungshin Yim
Apr 1, 2020·Immunopharmacology and Immunotoxicology·Zhe GeShuzhe Ding
Jun 21, 2020·Cancers·Dandan Wang, Subramaniam Malarkannan
Aug 3, 2020·Bioorganic & Medicinal Chemistry Letters·Nannan WuZhongjin Yang
Oct 13, 2020·Pharmacology & Therapeutics·Laura MasuelliRoberto Bei
Apr 23, 2021·Advanced Drug Delivery Reviews·Juan GuanChangyou Zhan
Nov 10, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Zahra MemarianiAroona Chabra

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