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

  • Authors:
    • Cho Hee Kim
    • A. Ra Ko
    • Su Yeon Lee
    • Hyun Min Jeon
    • Sun Mi Kim
    • Hye Gyeong Park
    • Song Iy Han
    • Ho Sung Kang
  • View Affiliations

  • Published online on: January 1, 2010     https://doi.org/10.3892/ijo_00000482
  • Pages: 117-124
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

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 H2O2 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.

Related Articles

Journal Cover

January 2010
Volume 36 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Kim, C.H., Ko, A.R., Lee, S.Y., Jeon, H.M., Kim, S.M., Park, H.G. ... Kang, H.S. (2010). Hypoxia switches glucose depletion-induced necrosis to phosphoinositide 3-kinase/Akt-dependent apoptosis in A549 lung adenocarcinoma cells. International Journal of Oncology, 36, 117-124. https://doi.org/10.3892/ijo_00000482
MLA
Kim, C. H., Ko, A. R., Lee, S. Y., Jeon, H. M., Kim, S. M., Park, H. G., Han, S. I., Kang, H. S."Hypoxia switches glucose depletion-induced necrosis to phosphoinositide 3-kinase/Akt-dependent apoptosis in A549 lung adenocarcinoma cells". International Journal of Oncology 36.1 (2010): 117-124.
Chicago
Kim, C. H., Ko, A. R., Lee, S. Y., Jeon, H. M., Kim, S. M., Park, H. G., Han, S. I., Kang, H. S."Hypoxia switches glucose depletion-induced necrosis to phosphoinositide 3-kinase/Akt-dependent apoptosis in A549 lung adenocarcinoma cells". International Journal of Oncology 36, no. 1 (2010): 117-124. https://doi.org/10.3892/ijo_00000482