Oroxylin A inhibits the generation of Tregs in non-small cell lung cancer

// Le Shen 1, * , Lu-Lu Zhang 2, * , Hui Li 1 , Xiao Liu 1 , Xiao-Xuan Yu 1 , Po Hu 1 , Hui Hui 1 , Qing-Long Guo 1 and Shuai Zhang 3 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, People’s Republic of China 2 Department of Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, People’s Republic of China 3 Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing 210009, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Shuai Zhang, email: Dr_zhangshuai@163.com Qing-Long Guo, email: anticancer_drug@163.com Hui Hui, email: moyehh@163.com Keywords: oroxylin A, tregs, TGF-β1, NF-κB Received: January 23, 2017      Accepted: March 22, 2017      Published: April 19, 2017 ABSTRACT Oroxylin A (OA), a naturally occurring monoflavonoid isolated from Scutellariae radix , has previously been reported to inhibit the proliferation of several cancer cell lines. CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) play an important role in maintenance of immunologic self-tolerance. Tregs also increase in cancer and take part in suppressing antitumor immune responses. Here, we explored how OA affected the Tregs in lung cancer environment and the involved underlying mechanism. It is found that OA reversed the generation of Tregs induced by H460 lung cancer cells co-culture. Furthermore, in vivo , OA reduced tumor formation rate and attenuated Foxp3 expression in tumor-infiltrating lymphocytes. We also found that transforming growth factor-β1 (TGF-β1) neutralizing antibody reversed the enhancement of Treg number and expression of p-Smad3ˎp-p38ˎp-JNKˎp-ERK1/2 in the co-culture model. Moreover, OA reduced the secretion of TGF-β1 and down-regulated the activation of NF-κB signaling in H460 cells. OA also inhibited Treg activity by a direct inhibition of the T cells’ response to TGF-β1. In conclusion, our study demonstrated that OA inhibits the generation of Tregs in lung cancer environment by inhibiting the T cells’ response to TGF-β1 and decreasing the secretion of TGF-β1 in lung cancer cells via NF-κB signaling.