title: Silibinin induces mitochondrial NOX4-mediated endoplasmic reticulum stress response and its subsequent apoptosis.
abstract: Silibinin, a biologically active compound of milk thistle, has chemopreventive effects on cancer cell lines. Recently it was reported that silibinin inhibited tumor growth through activation of the apoptotic signaling pathway. Although various evidences showed multiple signaling pathways of silibinin in apoptosis, there were no reports to address the clear mechanism of ROS-mediated pathway in prostate cancer PC-3 cells. Several studies suggested that reactive oxygen species (ROS) play an important role in various signaling cascades, but the primary source of ROS was currently unclear.
  
  
  
  The effect of silibinin was investigated on cell growth of prostate cell lines by MTT assay. We examined whether silibinin induced apoptosis through production of ROS using flow cytometry. Expression of apoptosis-, endoplasmic reticulum (ER)-related protein and gene were determined by western blotting and RT-PCR, respectively.
  
  
  
  Results showed that silibinin triggered mitochondrial ROS production through NOX4 expression and finally led to induce apoptosis. In addition, mitochondrial ROS caused ER stress through disruption of Ca(2+) homeostasis. Co-treatment of ROS inhibitor reduced the silibinin-induced apoptosis through the inhibition of NOX4 expression, resulting in reduction of both Ca(2+) level and ER stress response.
  
  
  
  Taken together, silibinin induced mitochondrial ROS-dependent apoptosis through NOX4, which is associated with disruption of Ca(2+) homeostasis and ER stress response. Therefore, the regulation of NOX4, mitochondrial ROS producer, could be a potential target for the treatment of prostate cancer.
authors.affiliation: Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan, 626-870, Republic of Korea.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 689-798, Republic of Korea.
authors.forename: Kwang-Youn
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan, 626-870, Republic of Korea.|Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Pusan National University, Yangsan, 626-870, Republic of Korea.
authors.forename: Sun-Nyoung
authors.initials: SN
authors.lastname: Yu
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 689-798, Republic of Korea.
authors.forename: Young-Kyo
authors.initials: YK
authors.lastname: Seo
authors.affiliation: Department of Food Science, International University of Korea, Jinju, 660-759, Republic of Korea.
authors.forename: Sung-Sik
authors.initials: SS
authors.lastname: Chun
authors.affiliation: Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Pusan National University, Yangsan, 626-870, Republic of Korea.|Department of Parasitology, Pusan National University School of Medicine, Yangsan, 626-870, Republic of Korea.
authors.forename: Hak-Sun
authors.initials: HS
authors.lastname: Yu
authors.affiliation: Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan, 626-870, Republic of Korea. ahnsc@pusan.ac.kr.|Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Pusan National University, Yangsan, 626-870, Republic of Korea. ahnsc@pusan.ac.kr.
authors.forename: Soon-Cheol
authors.initials: SC
authors.lastname: Ahn
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D012838:Silymarin; D000077385:Silybin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human
keywords: Apoptosis; Ca2+; Endoplasmic reticulum stress; NOX; Reactive oxygen species; Silibinin