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.
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.
Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.|School of Chinese medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Ching-Yuan
CY
Wu
Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.|School of Chinese medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Yao-Hsu
YH
Yang
Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.
Yin-Yin
YY
Lin
Department of Hematology and oncology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.
Feng-Che
FC
Kuan
Department of Pharmacy, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.
Yu-Shin
YS
Lin
Department of Urology, Chang Gung Memorial Hospital at Chiayi, Puzi City, Taiwan.|Chang Gung University of Science and Technology, Chia-Yi, Taiwan.
Wei-Yu
WY
Lin
Department of Chinese Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan.
Ming-Yen
MY
Tsai
Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.
Jia-Jing
JJ
Yang
Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.
Yu-Ching
YC
Cheng
Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.
Li-Hsin
LH
Shu
Department of Hematology and oncology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.
Ming-Chu
MC
Lu
Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan.|Hormone Research Center, Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
Yun-Ju
YJ
Chen
School of Chinese medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Kuan-Der
KD
Lee
Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan.|Hormone Research Center, Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
Hong-Yo
HY
Kang
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000378:metabolism; D018920:Coculture Techniques; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008516:Medicine, Chinese Traditional; D051379:Mice; D010616:Phenanthrenes / Q000494:pharmacology*; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D027561:Salvia miltiorrhiza / Q000737:chemistry; D000071250:Snail Family Transcription Factors / Q000096:biosynthesis; D016896:Treatment Outcome; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; C000604407:SNAI1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071250:Snail Family Transcription Factors; C066737:RHOA protein, human; C028972:dan-shen root extract; C046825:dihydroisotanshinone I; D020742:rhoA GTP-Binding Protein
CCL2; STAT3; Skp2; dihydroisotanshinone I; prostate cancer