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
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Ching-Yuan Wu1,2, Yao-Hsu Yang1,2, Yin-Yin Lin1, Feng-Che Kuan3, Yu-Shin Lin4, Wei-Yu Lin5,6, Ming-Yen Tsai7, Jia-Jing Yang1, Yu-Ching Cheng1, Li-Hsin Shu1, Ming-Chu Lu3, Yun-Ju Chen8,9, Kuan-Der Lee2 and Hong-Yo Kang8,9
1Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
2School of Chinese medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
3Department of Hematology and oncology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
4Department of Pharmacy, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
5Department of Urology, Chang Gung Memorial Hospital at Chiayi, Puzi City, Taiwan
6Chang Gung University of Science and Technology, Chia-Yi, Taiwan
7Department of Chinese Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan
8Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan
9Hormone Research Center, Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan
Kuan-Der Lee, email: [email protected]
Hong-Yo Kang, email: [email protected]
Keywords: dihydroisotanshinone I, STAT3, prostate cancer, Skp2, CCL2
Received: May 10, 2016 Accepted: January 10, 2017 Published: February 01, 2017
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.
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