Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells.
Accumulation of reactive oxygen species (ROS) such as hydrogen peroxide (H(2)O(2)) is an oxidative stress response, which induced various defense mechanisms or programmed cell death (PCD). As one of the major types of PCD, autophagy has been observed in response to several anticancer drugs and demonstrated to be responsible for cell death. To date, however, the exact mechanism by which ROS regulates autophagy is still poorly understood. Thus, the purposes of this study were to elucidate how H(2)O(2) exerts its cytotoxic effects on malignant glioma U251 cells and to uncover the molecular mechanism that might be involved. Here, we show that H(2)O(2)-induced autophagy and apoptosis in U251 cells are mediated through the Beclin 1 and Akt/mTOR pathways. Accumulation of ROS leads to changes in mitochondrial permeability with loss of mitochondrial membrane potential and disruption of mitochondrial dynamics at a transcriptional level of fission and fusion. Overexpression of cellular Bcl-2 partially inhibited autophagy through both the Beclin 1 and the Akt/mTOR pathways and led to recovery of mitochondrial dynamics. When autophagy was prevented at an early stage by 3-methyladenine, apoptosis significantly increased. Our data provide the first evidence that H(2)O(2) induces autophagy through interference with the Beclin 1 and Akt/mTOR signaling pathways and is regulated by the anti-apoptotic gene Bcl-2 in glioma U251 cells.
Zhang
Hongyu
H
Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China.
Kong
Xiaoxia
X
Kang
Jinsong
J
Su
Jing
J
Li
Yang
Y
Zhong
Jiateng
J
Sun
Liankun
L
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014162:Transfection
D000225:Adenine; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D006861:Hydrogen Peroxide; D008565:Membrane Proteins; D016877:Oxidants; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D058570:TOR Serine-Threonine Kinases; C491997:BECN1 protein, human; C025946:3-methyladenine; C546842:MTOR protein, human