title: Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways.
abstract: Metastasis is one of the most important factors related to prostate cancer therapeutic efficacy. In previous studies, shikonin, an active naphthoquinone isolated from the Chinese medicine Zi Cao, has various anticancer activities both in vivo and in vitro. However, the mechanisms underlying shikonin's anticancer activity are not fully elucidated on prostate cancer cells. In the present study, we aimed to investigate the potential effects of shikonin on prostate cancer cells and the underlying mechanisms by which shikonin exerted its actions. With cell proliferation, flow cytometric cell cycle, migration and invasion assays, we found that shikonin potently suppressed PC-3 and DU145 cell growth by cell cycle arrest at the G2 phase and metastasis in a dose-dependent manner. Mechanically, we presented that shikonin could suppress the metastasis of PC-3 and DU145 cells via inhibiting the matrix metalloproteinase-2 (MMP-2) and MMP-9 expression and activation. In addition, shikonin significantly decreased the phosphorylation of AKT and mTOR in a dose-dependent manner while it induced extracellular signal-regulated kinase (ERK), p38 mitogen activated protein kinase (MAPK) and c-Jun N terminal kinase (JNK) phosphorylation. Further investigation of the underlying mechanism revealed that shikonin also induced the production of reactive oxygen species (ROS) that was reversed by the ROS scavenger dithiothreitol (DTT). Additionally, DTT reversed the shikonin induced activation of ERK1/2, thereby maintaining MMP-2 and MMP-9 expression and restoring cell metastasis. Together, shikonin inhibits aggressive prostate cancer cell migration and invasion by reducing MMP-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways and presents a potential novel alternative agent for the treatment of human prostate cancer.
authors.affiliation: Department of Central Laboratory, 97th Hospital of PLA, 226 Tongshang Road, Xuzhou 221004, China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Central Laboratory, 97th Hospital of PLA, 226 Tongshang Road, Xuzhou 221004, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Central Laboratory, 97th Hospital of PLA, 226 Tongshang Road, Xuzhou 221004, China.
authors.forename: Junquan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Central Laboratory, 97th Hospital of PLA, 226 Tongshang Road, Xuzhou 221004, China.
authors.forename: Zhonghai
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Central Laboratory, 97th Hospital of PLA, 226 Tongshang Road, Xuzhou 221004, China.
authors.forename: Xiliang
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Central Laboratory, 97th Hospital of PLA, 226 Tongshang Road, Xuzhou 221004, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Lv
authors.affiliation: Department of Central Laboratory, 97th Hospital of PLA, 226 Tongshang Road, Xuzhou 221004, China. Electronic address: chenfuxingtitc@163.com.
authors.forename: Fuxing
authors.initials: F
authors.lastname: Chen
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D009285:Naphthoquinones; D017382:Reactive Oxygen Species; C016101:shikonin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Human prostate cancer; Invasion; Matrix metalloproteinase; Migration; Shikonin