Hypoxia switches glucose depletion-induced necrosis to phosphoinositide 3-kinase/Akt-dependent apoptosis in A549 lung adenocarcinoma cells

Department of Molecular Biology, College of Natural Sciences, and Research Institute of Genetic Engineering, Pusan National University, Pusan 609-735, Korea.
International Journal of Oncology (Impact Factor: 3.03). 01/2010; 36(1):117-24. DOI: 10.3892/ijo_00000482
Source: PubMed


In solid tumours, necrosis is commonly found in the core region in response to metabolic stress that results from oxygen and glucose depletion (OGD) due to insufficient vascularization and has been implicated in tumour progression. We have previously shown that metabolic stress due to glucose depletion (GD) induces necrosis and HMGB1 release through mitochondrial ROS production in A549 lung adenocarcinoma cells. In this study, we examined the effects of hypoxia on GD-induced necrosis and show that hypoxia prevented GD-induced mitochondrial ROS production, HMGB1 release, and necrosis and switched the cell death mode to apoptosis that is dependent on caspase-3 and -9. We further found that inhibition of ERK1/2 by U0126 abolished the effects of hypoxia to switch the cell death mode and to suppress mitochondrial ROS production, indicating an important role(s) of the ERK pathway in cell death mode determination. We also found that during OGD-induced apoptosis the prosurvival protein kinase Akt is activated and inhibition of Akt by the phosphoinositide 3-kinase (PI3K) inhibitors LY294002 and wortmannin prevent OGD-induced apoptosis, caspase-3 and -9 activation, and nuclear translocation of AIF and EndoG. Similar inhibitory effects of PI3K inhibitors were observed in A549 cells that underwent apoptosis when treated with GD in the presence of NAC (a general antioxidant) or catalase (a H(2)O(2) scavenger), or in the presence of active PKC by treatment with phorbol-12-myristate-13-acetate, indicating a crucial role(s) of the PI3K-Akt pathway in OGD-indcued apoptosis. In conclusion, our results demonstrate that hypoxia switches GD-induced necrosis to apoptosis and ERK1/2 and PI3K-Akt exert anti-necrotic and pro-apoptotic activities in the cell death, respectively.

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    • "It can be explained by the different HSCs status (intermediate) partly, and why the ability of JNK inhibitor to enhance the HSCs sensitization to induced apoptosis[31] did't display probably is that HMGB1 actually didn't induce apoptosis. Till now,HMGB1 has been found to modulate functions of many cell types, such as human airway epithelial cells, leukemia cells, lung adenocarcinoma cells, through PI3K/Akt signal pathway [40]–[42]. On the other hand, human activated HSCs utilize components of TLR4 signal transduction cascade to stimulate NF-κB and JNK and up-regulate chemokines and adhesion molecules [36]. As to other cell line like Kuffer cells, HMGB1 can induce proinflammatory cytokines production after sever burn injury, largely dependent on TLRs-dependent MAPKs/NF-kB signal pathway[43]. "
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    • "We thus hypothesize that, in conditions of serum starvation, rutin could trigger apoptosis of leukemic cells through both their restored Akt and metabolic activities and inhibition of the pro-survival GSK3␤ pathway [2]. Indeed, GSK3␤-induced cytotoxicity has been previously linked to inhibition of NF-␬B and mitochondrial destabilization [2] [23] and despite its well-known pro-survival role, the PI3K/Akt pathway could exert pro-apoptotic activity in altered metabolic conditions [24] [25]. "
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    • "Trans resveratrol is a naturally occurring compound and is enriched in grapes, mulberries and in red wine, and possesses a strong antioxidant activity capable of protecting against oxidative damage (Robb and Stuart, 2010; Sakata et al., 2010). In vivo, dietary administration of trans resveratrol to mice (Kim et al., 2010) or rats (Halliwell and Gutteridge, 2000) confers protection against acute brain injury caused by transient middle cerebral artery occlusion or cardiac arrest, respectively. Dietary trans resveratrol supplementation reduces plaque formation in the brains of transgenic mouse model of Alzheimer's disease (Sakata et al., 2010). "
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