Carcinogenesis Advance Access originally published online on May 4, 2006
Carcinogenesis 2006 27(10):2047-2058; doi:10.1093/carcin/bgl051
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress
Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences Raebareli Road, Lucknow, 226 014, India
1 Tissue Culture Laboratory, Central Drug Research Institute Mahatma Gandhi Marg, Lucknow, 226 001, India
2 Electron Microscopy Division, Central Drug Research Institute Mahatma Gandhi Marg, Lucknow, 226 001, India
*To whom correspondence should be addressed. Tel: +91 522 2668700 ext. 2368; Fax: +91 522 2668017; Email: madangodbole{at}yahoo.co.in
N-(4-Hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid is under clinical evaluation as a therapeutic agent in a variety of cancers. Its mechanism(s) of action involves multiple overlapping pathways that still remain unclear. In glioma cells its mechanism of action is not well elucidated. Here, we show that 4-HPR and not all-trans retinoic acid and 9-cis retinoic acid effectively induce apoptosis in glioma cells. 4-HPR-induced apoptosis is associated with hydroperoxide production and loss of mitochondrial membrane potential (
m). Ultrastructural changes further indicate 4-HPR-induced mitochondrial swelling, endoplasmic reticulum (ER) dilation as well as close proximity of mitochondria and ER. As suggested by dilated ER, 4-HPR treatment increased the free cytosolic Ca2+ as well as mitochondrial Ca2+. Chelation of extracellular Ca2+ by EGTA did not prevent Ca2+ elevation, thus suggesting involvement of intracellular calcium stores in the release. Buffering of intracellular calcium by BAPTA-AM did not prevent 4-HPR-induced apoptosis; however, blocking the release of Ca2+ from ER by heparin inhibited apoptosis, indicating the role of depletion of Ca2+ from ER stores in apoptosis. 4-HPR treatment also resulted in an increase in Bax levels along with its translocation to mitochondria that promote mitochondrial membrane permeabilization. 4-HPR-induced apoptosis was further associated with the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol and nucleus, respectively, along with caspase-3 and caspase-7 activation. However, AIF nuclear translocation, peripheral chromatin condensation and apoptosis were not completely prevented by general caspase inhibitors, thus suggesting involvement of a caspase-dependent and caspase-independent pathway in 4-HPR-induced apoptosis. Taken together, these results suggest the role of mitochondrial-mediated pathway and ER stress as a key event in 4-HPR-induced apoptosis in glioma cells.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  V. Appierto, P. Tiberio, M. G. Villani, E. Cavadini, and F. Formelli PLAB induction in fenretinide-induced apoptosis of ovarian cancer cells occurs via a ROS-dependent mechanism involving ER stress and JNK activation Carcinogenesis, May 1, 2009; 30(5): 824 - 831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Oh and S.-C. Lim Endoplasmic Reticulum Stress-Mediated Autophagy/Apoptosis Induced by Capsaicin (8-Methyl-N-vanillyl-6-nonenamide) and Dihydrocapsaicin is Regulated by the Extent of c-Jun NH2-Terminal Kinase/Extracellular Signal-Regulated Kinase Activation in WI38 Lung Epithelial Fibroblast Cells J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 112 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-D. Lin, S. Chen, P. Yue, W. Zou, D. M. Benbrook, S. Liu, T. C. Le, K. D. Berlin, F. R. Khuri, and S.-Y. Sun CAAT/Enhancer Binding Protein Homologous Protein-Dependent Death Receptor 5 Induction Is a Major Component of SHetA2-Induced Apoptosis in Lung Cancer Cells Cancer Res., July 1, 2008; 68(13): 5335 - 5344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-C. Wang, S. K. Kulp, D. Wang, C.-C. Yang, A. M. Sargeant, J.-H. Hung, Y. Kashida, M. Yamaguchi, G.-D. Chang, and C.-S. Chen Targeting Endoplasmic Reticulum Stress and Akt with OSU-03012 and Gefitinib or Erlotinib to Overcome Resistance to Epidermal Growth Factor Receptor Inhibitors Cancer Res., April 15, 2008; 68(8): 2820 - 2830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Li, T. Zhang, H. Dai, G. Liu, H. Wang, Y. Sun, Y. Zhang, and Z. Ge Endoplasmic reticulum stress is involved in myocardial apoptosis of streptozocin-induced diabetic rats J. Endocrinol., March 1, 2008; 196(3): 565 - 572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tiwari, V. K. Bajpai, A. A. Sahasrabuddhe, A. Kumar, R. A. Sinha, S. Behari, and M. M. Godbole Inhibition of N-(4-hydroxyphenyl)retinamide-induced autophagy at a lower dose enhances cell death in malignant glioma cells Carcinogenesis, March 1, 2008; 29(3): 600 - 609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. S. Collingwood, E. V. Smirnova, M. Bogush, N. Carpino, R. S. Annan, and A. Y. Tsygankov T-cell Ubiquitin Ligand Affects Cell Death through a Functional Interaction with Apoptosis-inducing Factor, a Key Factor of Caspase-independent Apoptosis J. Biol. Chem., October 19, 2007; 282(42): 30920 - 30928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Anding, J. S. Chapman, D. W. Barnett, R. W. Curley Jr., and M. Clagett-Dame The Unhydrolyzable Fenretinide Analogue 4-Hydroxybenzylretinone Induces the Proapoptotic Genes GADD153 (CHOP) and Bcl-2-Binding Component 3 (PUMA) and Apoptosis that Is Caspase- Dependent and Independent of the Retinoic Acid Receptor Cancer Res., July 1, 2007; 67(13): 6270 - 6277. [Abstract] [Full Text] [PDF]
|
|