Cordycepin and a preparation from Cordyceps militaris inhibit malignant transformation and proliferation by decreasing EGFR and IL-17RA signaling in a murine oral cancer model

// Peng-Yang Hsu 1 , Yueh-Hsin Lin 2 , Erh-Ling Yeh 1 , Hui-Chen Lo 3 , Tai-Hao Hsu 1 and Che-Chun Su 1, 4, 5, 6 1 Department of Bioindustry Technology, Da-Yeh University, Datsuen, Taiwan 2 Department of Nutrition and Dietetics, Changhua Christian Hospital, Taiwan 3 Department of Nutritional Science, Fu Jen Catholic University, Taiwan 4 Graduate Institute of Statistics and Information Science, National Changhua University of Education, Taiwan 5 Department of Internal Medicine, Changhua Christian Hospital, Taiwan 6 Laboratory of Immunology, Changhua Christian Hospital, Taiwan Correspondence to: Che-Chun Su, email: 115025@cch.org.tw Tai-Hao Hsu, email: th0123@mail.dyu.edu.tw Keywords: Cordyceps militaris, cordycepin, oral cancer, EGFR, IL-17A tumoricidal activity Received: August 13, 2017      Accepted: September 20, 2017      Published: October 04, 2017 ABSTRACT Cordyceps militaris (CM) and its active ingredient cordycepin have been reported to inhibit tumor growth, but the mechanisms are not fully understood. This study used a mouse model for oral cancer and a cell line, 4NAOC-1 derived from the model to study the mechanisms. Our results show that a CM preparation (CMP) can significantly inhibit tumor development and malignant transformation in the model. In vitro data indicate that CMP and cordycepin can inhibit 4NAOC-1 cell proliferation, either anchorage-dependent or -independent. Cordycepin can also increase cell apoptosis, and decrease cell mitosis and EGFR signaling. In accordance, CMP treatment can significantly decrease the levels of ki-67 and EGFR signaling molecules in cancer tissues. We also found that the levels of IL-17A in cancer tissues of control mice were significantly increased, and CMP inhibited these levels. IL-17A can stimulate cancer cell proliferation, which can be suppressed by cordycepin. Furthermore, cordycepin can reduce the expression of IL-17RA and its downstream signaling molecules. Moreover, CMP and cordycepin can significantly decrease IL-17A production in vitro and in vivo . Finally, CMP and its ingredients can enhance tumoricidal activities with increase in IFN-γ and TNFα, and decrease PD-L1 expression. In conclusion, CMP and its ingredient cordycepin can inhibit tumor growth and malignant transformation in a mouse model for oral cancer via inhibition of EGFR- and IL-17RA-signaling and enhancement of anti-tumor immunity.