Protein kinase C-ERK1/2 signal pathway switches glucose depletion-induced necrosis to apoptosis by regulating superoxide dismutases and suppressing reactive oxygen species production in A549 lung cancer cells
✍ Scribed by Cho Hee Kim; Song Iy Han; Su Yeon Lee; Hyun Suk Youk; Ji Young Moon; Hong Quan Duong; Min Jung Park; Young Mi Joo; Hye Gyeong Park; Yung Jin Kim; Mi Ae Yoo; Sung-Chul Lim; Ho Sung Kang
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 832 KB
- Volume
- 211
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Cells typically die by either apoptosis or necrosis. However, the consequences of apoptosis and necrosis are quite different for a whole organism. In the case of apoptosis, the cell content remains packed in the apoptotic bodies that are removed by marcrophages, and thereby inflammation does not occur; during necrosis, the cell membrane is ruptured, and the cytosolic constituents are released into the extracellular space provoking inflammation. Recently, inflammation and necrosis have been suggested to promote tumor growth. We investigated the molecular mechanism underlying cell death in response to glucose depletion (GD), a common characteristic of the tumor microenvironment. GD induced necrosis through production of reactive oxygen species (ROS) in A549 lung carcinoma cells. Inhibition of ROS production by N‐acetyl‐L‐cysteine and catalase prevented necrosis and switched the cell death mode to apoptosis that depends on mitochondrial death pathway involving caspase‐9 and caspase‐3 activation, indicating a critical role of ROS in determination of GD‐induced cell death mode. We demonstrate that protein kinase C‐dependent extracellular regulated kinase 1/2 (ERK1/2) activation also switched GD‐induced necrosis to apoptosis through inhibition of ROS production possibly by inducing manganese superoxide dismutase (SOD) expression and by preventing GD‐induced degradation of cupper zinc SOD. Thus, these results suggest that GD‐induced cell death mode is determined by the protein kinase C/ERK1/2 signal pathway that regulates MnSOD and CuZnSOD and that these antioxidants may exert their known tumor suppressive activities by inducing necrosis‐to‐apoptosis switch. J. Cell. Physiol. 211: 371–385, 2007. © 2007 Wiley‐Liss, Inc.