Differential involvement of reactive oxygen species in apoptosis induced by two classes of selenium compounds in human prostate cancer cells

• Published in: International journal of cancer 2007-05, Vol.120 (9), p.2034-2043
• Main Authors: Li, Guang‐Xun, Hu, Hongbo, Jiang, Cheng, Schuster, Todd, Lü, Junxuan
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Androgens - pharmacology; Antioxidants - pharmacology; apoptosis; Apoptosis - drug effects; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Caspases - physiology; Cell Line, Tumor; Chemical agents; DNA Breaks; DNA damage; Humans; Male; Medical sciences; Nephrology. Urinary tract diseases; Organoselenium Compounds - pharmacology; p53; prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Reactive Oxygen Species; ROS; selenium; Signal Transduction; Sodium Selenite - pharmacology; Tumor Suppressor Protein p53 - metabolism; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.22480

Selenium is a promising chemopreventive agent for prostate cancer, possibly via an induction of apoptosis. Earlier studies have shown that selenite induces DNA single strand breaks (SSBs), reactive oxygen species (ROS), p53 Ser‐15 phosphorylation and caspase‐dependent and ‐independent apoptosis, whereas a methylselenol precursor methylseleninic acid (MSeA) induces caspase‐mediated apoptosis regardless of p53 status. Here we address three main questions: What types of ROS are induced by selenite vs. MSeA in LNCaP (p53 wild type, androgen‐responsive) and DU145 (mutant p53, androgen‐independent) prostate cancer cells? Does ROS generation depend on androgen signaling? What are the relationships among ROS, DNA SSBs, p53 and caspases? We show that selenite (5 μM) induced superoxide and hydrogen peroxide in LNCaP cells much more than in DU145 cells and the ROS generation was not affected by physiological androgen stimulation. MSeA (10 μM) induced apoptosis without either type of ROS in both cell lines. In LNCaP cells, we established superoxide as a primary mediator for selenite‐induced DNA SSBs, p53 activation and caspase‐mediated apoptosis. Furthermore a p53‐dominant negative mutant attenuated selenite‐induced ROS, leading to a proportionate protection against apoptosis. The results support the p53‐mitochondria axis in a feedback loop for sustaining superoxide production to lead to efficient caspase‐mediated apoptosis by selenite. In contrast, caspase‐mediated apoptosis induced by MSeA does not involve ROS induction. Since p53 is frequently mutated or deleted in prostate cancer and many other cancers, our results suggest that genotoxic vs. nongenotoxic classes of selenium may exert differential apoptosis efficacy depending on the p53 status of the cancer cells. © 2007 Wiley‐Liss, Inc.