Oxidative Stress Induces Parallel Autophagy and Mitochondria Dysfunction in Human Glioma U251 Cells

Abstract

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.

Induction of apoptosis by 7-piperazinethylchrysin in HCT-116 human colon cancer cells

“…We speculate that ROS might modulate the cellular distribution and content of Bcl-2. Generation of ROS may contribute to mitochondrial damage and lead to cell death by acting as apoptotic signaling molecules (36)(37)(38)(39). In the present study, we found that in addition to its effect on ∆Ψm, 7-PEC caused an increase in ROS production in HCT-116 cells.…”

Tgf-β1 induces autophagy and promotes apoptosis in renal tubular epithelial cells

“…Interestingly, oxidative stress has also been reported to induce programmed cell death (PCD) including apoptosis or autophagy (3). Some evidence showed that ROS induces autophagy through the class III PI3K/Beclin1 signaling pathways (5). In the present study we showed that TGF-β1 induced expression of NADPH oxidase and generation of cellular ROS in a dose-and time dependent manner in HRPTEpiCs.…”

“…The proautophagic effect of TGF-β1 was associated with the expression of LC3-II and transcriptional activation of Atg genes. Formation of autophagosomes includes the formation of preautophagosomal membrane (phagophore or isolation membrane) which is initiated by class III phosphoinositide 3-kinase (PI3K) complex that includes Beclin1, and the elongation of the isolation membrane which is stimulated by two ubiquitin-like conjugation systems (Atg12-Atg5 and LC3-phosphatidylethanolamine) (3,5). Recent studies have indicated that activation of Beclin1 is consistently associated with induction of autophagy in cancer cells (17).…”

“…Autophagy is usually regarded as a protective mechanism for cell survival under various conditions including nutrient deprivation and hypoxia (4). However, increasing evidence suggests that in response to excessive stress autophagy may be detrimental and can lead to cell death (5). Excessive autophagic activity may lead to cellular dysfunctions and induce death by destroying a large proportion of the cytosol and organelles, especially the mitochondria and the endoplasmic reticulum (ER) (6,7).…”

Mitochondrial network in the heart

“…ROS can induce the opening of mPTP (Zorov et al, 2000), disrupt mitochondrial depolarization (Skulachev et al, 2004), and finally result in mitochondrial fragmentation (Zorov et al, 2000;Zhang et al, 2009). Mitochondrial damages, such as photo damage or the mitochondria-targeted oxidants, induce a boost of ROS, cause the loss of membrane potential and interruption of mitochondrial fission (Mai et al, 2010;Schmidt et al, 2010;Mai et al, 2012).…”