title: Tanshinone IIA inhibits human prostate cancer cells growth by induction of endoplasmic reticulum stress in vitro and in vivo.
abstract: BACKGROUND
  Tanshinone IIA (Tan-IIA) is one of the major lipophilic components isolated from the root of Salviae Miltiorrhizae Radix. We explored the mechanisms of cell death induced by Tan-IIA treatment in prostate cancer cells in vitro and in vivo.
  
  
  METHODS
  Cells were treated with Tan-IIA and growth inhibition was assessed. Cell cycle profiles after Tan-IIA treatment were determined by flow cytometry. Expression levels of cell cycle regulatory proteins and apoptosis-related proteins were determined after Tan-IIA treatment. Expression levels of endoplasmic reticulum (ER) stress-regulated genes were determined to investigate their role in Tan-IIA-induced cell death. GADD153 expression was knocked down by small interfering RNA (siRNA) transfection. Rate of cell death and proliferation was obtained by 3-(4,5-dimethyl thizol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Antitumor activity of Tan-IIA was performed in LNCaP xenograft model.
  
  
  RESULTS
  Our results showed that Tan-IIA caused prostate cancer cell death in a dose-dependent manner, and cell cycle arrest at G0/G1 phase was noted, in LNCaP cells. The G0/G1 phase arrest correlated with increase levels of CDK inhibitors (p16, p21 and p27) and decrease of the checkpoint proteins. Tan-IIA also induced ER stress in prostate cancer cells: activation and nuclear translocation of GADD153/CCAAT/enhancer-binding protein-homologous protein (CHOP) were identified, and increased expression of the downstream molecules GRP78/BiP, inositol-requiring protein-1α and GADD153/CHOP were evidenced. Blockage of GADD153/CHOP expression by siRNA reduced Tan-IIA-induced cell death in LNCaP cells. Tan-IIA also suppressed LNCaP xenograft tumor growth, causing 86.4% reduction in tumor volume after 13 days of treatment.
  
  
  CONCLUSIONS
  Our findings suggest that Tan-IIA causes G0/G1 cell cycle arrest in LNCaP cells and its cytotoxicity is mediated at least partly by ER stress induction. These data provide evidence supporting Tan-IIA as a potential anticancer agent by inducing ER stress in prostate cancer.
authors.affiliation: Department of Research, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan.
authors.forename: S C
authors.initials: SC
authors.lastname: Chiu
authors.forename: S Y
authors.initials: SY
authors.lastname: Huang
authors.forename: S P
authors.initials: SP
authors.lastname: Chen
authors.forename: C C
authors.initials: CC
authors.lastname: Su
authors.forename: T L
authors.initials: TL
authors.lastname: Chiu
authors.forename: C Y
authors.initials: CY
authors.lastname: Pang
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D004365:Drugs, Chinese Herbal; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C021751:tanshinone