Anti-cancer effect of danshen and dihydroisotanshinone I on prostate cancer: targeting the crosstalk between macrophages and cancer cells via inhibition of the STAT3/CCL2 signaling pathway

// Ching-Yuan Wu 1, 2 , Yao-Hsu Yang 1, 2 , Yin-Yin Lin 1 , Feng-Che Kuan 3 , Yu-Shin Lin 4 , Wei-Yu Lin 5, 6 , Ming-Yen Tsai 7 , Jia-Jing Yang 1 , Yu-Ching Cheng 1 , Li-Hsin Shu 1 , Ming-Chu Lu 3 , Yun-Ju Chen 8, 9 , Kuan-Der Lee 2 and Hong-Yo Kang 8, 9 1 Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 2 School of Chinese medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan 3 Department of Hematology and oncology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 4 Department of Pharmacy, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 5 Department of Urology, Chang Gung Memorial Hospital at Chiayi, Puzi City, Taiwan 6 Chang Gung University of Science and Technology, Chia-Yi, Taiwan 7 Department of Chinese Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan 8 Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan 9 Hormone Research Center, Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan Correspondence to: Kuan-Der Lee, email: kdlee@cgmh.org.tw Hong-Yo Kang, email: hkang3@mail.cgu.edu.tw Keywords: dihydroisotanshinone I, STAT3, prostate cancer, Skp2, CCL2 Received: May 10, 2016     Accepted: January 10, 2017     Published: February 01, 2017 ABSTRACT Danshen (Salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine. In our study, the in vivo protective effect of danshen in prostate cancer patients was validated through data from the National Health Insurance Research Database in Taiwan. In vitro , we discovered that dihydroisotanshinone I (DT), a bioactive compound present in danshen, can inhibit the migration of both androgen-dependent and androgen-independent prostate cancer cells. In addition, we noted that DT substantially inhibited the migratory ability of prostate cancer cells in both a macrophage-conditioned medium and macrophage/prostate cancer coculture medium. Mechanistically, DT both diminished the ability of prostate cancer cells to recruit macrophages and reduced the secretion of chemokine (C-C motif) ligand 2 (CCL2) from both macrophages and prostate cancer cells in a dose-dependent manner. Moreover, DT inhibited the protein expression of p-STAT3 and decreased the translocation of STAT3 into nuclear chromatin. DT also suppressed the expression of tumor epithelial–mesenchymal transition genes, including RhoA and SNAI1. In conclusion, danshen can prolong the survival rate of prostate cancer patients in Taiwan. Furthermore, DT can inhibit the migration of prostate cancer cells by interrupting the crosstalk between prostate cancer cells and macrophages via the inhibition of the CCL2/STAT3 axis. These results may provide the basis for a new therapeutic approach toward the treatment of prostate cancer progression.