Tanshinone IIA Induces Mitochondria Dependent Apoptosis in Prostate Cancer Cells in Association with an Inhibition of Phosphoinositide 3-Kinase/AKT Pathway

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概要

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• Tanshinone IIA (Tan IIA; 14,16-epoxy-20-nor-5(10),6,8,13,15-abietapentaene-11,12-dione), a phytochemical derived from the roots of Salvia miltiorrhiza BUNGE, has been reported to posses anti-angiogenic, anti-oxidant, anti-inflammatory and apoptotic activities. However, the cancer growth inhibitory/cytocidal effects and molecular mechanisms in prostate cancer cells have not been well studied. In the present study, we demonstrate that Tan IIA significantly decreased the viable cell number of LNCaP (phosphate and tensin homolog (PTEN) mutant, high AKT, wild type p53) prostate cancer cells more sensitively than against the PC-3 (PTEN null, high AKT, p53 null) prostate cancer cells. Tan IIA significantly increased TdT-mediated dUTP nick-end labeling (TUNEL) positive index and sub-G1 DNA contents of treated cells, consistent with apoptosis. Tan IIA treatment led to cleavage activation of pro-caspases-9 and 3, but not pro-caspase-8, and cleavage of poly (ADP ribose) polymerase (PARP), a caspase-3 substrate. Additionally, Tan IIA treatment induced cytochrome c release from the mitochondria into the cytosol and reduced mitochondrial membrane potential and suppressed the expression of mitochondria protective Bcl-2 family protein Mcl-1L. Tan IIA reduced the expression of phosphoinositide 3-kinase (PI3K) p85 subunit, and the phosphorylation of AKT and mammalian target of rapamycin (mTOR) in a concentration-dependent manner. Moreover, the combination of Tan IIA and LY294002, a specific PI3K inhibitor, enhanced PARP cleavage of LNCaP and PC-3, but not in MDA-MB-231 breast cancer cells which do not contain detectable active AKT. The findings suggest that Tan IIA-induced apoptosis involves mitochondria intrinsic caspase activation cascade and an inhibition of the PI3K/AKT survival pathway.

著者

• KIM Sung-Hoon

  College of Oriental Medicine, Kyunghee University

• Jeong Soo-Jin

  College of Oriental Medicine, Kyung Hee University

• Lee Hyo-Jung

  College of Oriental Medicine, Kyung Hee University

• Lee Hyo-Jeong

  College of Oriental Medicine, Kyung Hee University

• Lee Hong-beom

  Division Of Ocean Science Korea Maritime University

• Kwon Tae-Rin

  College of Oriental Medicine, Kyung Hee University

• Lee Eun-Ok

  College of Oriental Medicine, Kyung Hee University

• Lee Hyo-jung

  Coll. Of Oriental Medicine Kyung Hee Univ.

• Won Suk-Hyun

  College of Oriental Medicine, Kyung Hee University

• Jung Deok-Beom

  College of Oriental Medicine, Kyung Hee University

• Shin Ji-Min

  College of Oriental Medicine, Kyung Hee University

• Yun Sun-Mi

  College of Oriental Medicine, Kyung Hee University

• Lee Min-Ho

  College of Life Sciences and Biotechnology, Kyung Hee University

• Choi Seung-Hoon

  College of Oriental Medicine, Kyung Hee University

• Lü Junxuan

  The Hormel Institute, University of Minnesota

• Kim Sung-Hoon

  College of Oriental Medicine, Kyung Hee University

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