Tanshinone IIA inhibits human prostate cancer cells growth by induction of endoplasmic reticulum stress in vitro and in vivo

被引:74
作者
Chiu, S. C. [1 ]
Huang, S. Y. [2 ,3 ]
Chen, S. P. [4 ]
Su, C. C. [5 ]
Chiu, T. L. [6 ]
Pang, C. Y. [7 ,8 ]
机构
[1] Taichung Tzu Chi Hosp, Buddhist Tzu Chi Med Fdn, Dept Res, Taichung, Taiwan
[2] Mackay Mem Hosp, Dept Ophthalmol, Hsinchu, Taiwan
[3] Jen Teh Jr Coll Med Nursing & Management, Dept Optometry, Miaoli, Taiwan
[4] Hualien Tzu Chi Hosp, Buddhist Tzu Chi Med Fdn, Tzu Chi Stem Cells Ctr, Hualien 970, Taiwan
[5] Changhua Christian Hosp, Dept Surg, Changhua, Taiwan
[6] Hualien Tzu Chi Hosp, Buddhist Tzu Chi Med Fdn, Neuromed Sci Ctr, Div Neurooncol, Hualien 970, Taiwan
[7] Hualien Tzu Chi Hosp, Buddhist Tzu Chi Med Fdn, Dept Med Res, Hualien 970, Taiwan
[8] Tzu Chi Univ, Sch Med, Inst Med Sci, Hualien, Taiwan
关键词
tanshinone IIA; LNCaP cells; ER stress; apoptosis; GADD153/CHOP; UNFOLDED PROTEIN RESPONSE; SALVIA-MILTIORRHIZA BUNGE; APOPTOSIS INDUCTION; CASPASE; 12; ACTIVATION; EXPRESSION; MECHANISM; DEATH; PATHWAYS; THERAPY;
D O I
10.1038/pcan.2013.38
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
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-1 alpha 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.
引用
收藏
页码:315 / 322
页数:8
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