Exposure of human leukemia NB4 cells to increasing concentrations of selenite switches the signaling from pro-survival to pro-apoptosis.
Selenium at low concentrations has a chemopreventive role against cancer, while at high concentrations, selenite exerts a direct antitumor effect. However, the mechanisms behind these effects remain elusive. In this study, we found that different concentrations of selenite triggered different signal pathways in human leukemia NB4 cells. Low concentrations of selenite elicited mild endoplasmic reticulum (ER) stress and mediated cell survival by activating unfolded protein response signaling, whereas high concentrations of selenite induced severe ER stress and caused cell death by activation of the pro-apoptotic transcription factors GADD153. In addition, selenite at low concentrations activated other anti-apoptotic pathways, such as AKT and ERK, whereas high concentrations of selenite induced activation of p53 and oxidative stress, which mediated the antitumor activity of selenite by causing mitochondrial dysfunction and caspase activation. These findings uncover the molecular mechanisms of the chemopreventive and antitumor effects of different concentrations of selenite.
Guan
Liying
L
National Laboratory of Medical Molecular Biology, Institute of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
Han
Bingshe
B
Li
Jian
J
Li
Zhushi
Z
Huang
Fang
F
Yang
Yang
Y
Xu
Caimin
C
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology*; D018384:Oxidative Stress; D015398:Signal Transduction / Q000187:drug effects; D018038:Sodium Selenite / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D051742:Transcription Factor CHOP; D018038:Sodium Selenite