title: Hydroxytyrosol promotes superoxide production and defects in autophagy leading to anti-proliferation and apoptosis on human prostate cancer cells.
abstract: Hydroxytyrosol, an important polyphenolic compound found in olive oil, has shown anti-tumor activity both in vitro and in vivo. However, effects of hydroxytyrosol on prostate cancer are largely unkown. We found that hydroxytyrosol preferentially reduces the viability of human prostate cancer cells (PC-3, DU145) compared to an immortalized non-malignant prostate epithelial cell line (RWPE-1). Exposure of PC-3 cells to 80 µmol/L hydroxytyrosol resulted in significant increases in both superoxide production and activation of apoptosis. These increases were accompanied by mitochondrial dysfunction, defects in autophagy, and activation of MAP kinases. Moreover, N-acetylcysteine (NAC), an efficient reactive oxygen species (ROS) scavenger, was able to reverse the hydroxytyrosol-induced effects of cell viability loss, defects in autophagy, and activation of apoptosis. This evidence suggests that ROS play a vital role in the loss of PC-3 cell viability. However, MAPK inhibitors including U0126 (for Erk1/2), SB203580 (for p38MAPK) and SP600125 (for JNK) did not decrease hydroxytyrosol-induced growth inhibition, suggesting that these kinases may not be required for the growth inhibitory effect of hydroxytyrosol. Moreover, addition of ROS scavengers (i.e. NAC, catalase, pyruvate, SOD) in the growth media can prevent hydroxytyrosol induced cell viability loss, suggesting that extracellular ROS (superoxide and hydrogen peroxide) facilitate the anti-proliferation effect of hydroxytyrosol in prostate cancer cells. The present work firstly shows that hydroxytyrosol induces apoptotic cell death and mitochondrial dysfunction by generating superoxide in PC-3 cells. This research presents preliminary evidence on the in vitro chemopreventive effect of hydroxytyrosol, and will contribute to further investigation of hydroxytyrosol as an anti-cancer agent.
authors.affiliation: Center for Mitochondrial Biology and Medicine, Xi'an Jiaotong University School of Life Science and Technology, Xi'an 710049, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Cui
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Feng
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Karin
authors.initials: K
authors.lastname: Wurtz
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.forename: Jiangang
authors.initials: J
authors.lastname: Long
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000975:Antioxidants / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D005638:Fruit / Q000737:chemistry; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D031658:Olea / Q000737:chemistry; D000069463:Olive Oil; D010626:Phenylethyl Alcohol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010938:Plant Oils / Q000737:chemistry; D011467:Prostate / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D016166:Free Radical Scavengers; D000069463:Olive Oil; D010938:Plant Oils; D047428:Protein Kinase Inhibitors; C005975:3,4-dihydroxyphenylethanol; D013481:Superoxides; D010626:Phenylethyl Alcohol