Selenite suppresses hydrogen peroxide-induced cell apoptosis through inhibition of ASK1/JNK and activation of PI3-K/Akt pathways.
The relationship between selenium and signal molecules has not been well elucidated. It was found that physiological concentration of selenite, 3 microM, reduced ASK1 activity and induced PI3-kinase (PI3-K)/Akt pathways in HT1080 cells. Duration of these signal molecules by selenite was much longer than that by growth factors and other stresses. The longer duration time of these signal molecules may be important to maintain normal functions against stresses. Selenite increased cell proliferation through up-regulation of Bcl-2 expression, mitochondrial membrane potential, adenosine triphosphate (ATP) generation, and glucose uptake mediated by PI3-K pathway. High concentration of H2O2 increased an apoptotic signal molecule, ASK1, which resulted in Bcl-2 down-regulation, membrane potential disruption, decreased ATP and glucose uptake, and activation of caspases. However, an antiapoptotic signal molecule, Akt, was activated also by H2O2, but duration of its activation was much shorter. Selenite blocked apoptosis induced by H2O2, which was related to blocking ASK1 and further stimulating PI3-kinase/Akt activities. Selenite blocked mitochondrial membrane potential disruption by 400 mM H2O2. Selenite also blocked caspase-9 and -3 activities and apoptosis induced by 500 microM H2O2, even after mitochondrial membrane potential disruption. These observations demonstrate that selenite increases cell proliferation and maintains cell survival by activating the antiapoptotic signal and blocking the apoptotic signal.
Yoon
Sang-Oh
SO
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea.
Kim
Moon-Moo
MM
Park
Soo-Jin
SJ
Kim
Dohoon
D
Chung
Jongkuleong
J
Chung
An-Sik
AS
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors*; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D018038:Sodium Selenite / Q000494:pharmacology*
D000255:Adenosine Triphosphate; D005947:Glucose; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D018038:Sodium Selenite; C494920:Akt1 protein, rat