Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm264
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Inhibition of N-(4-hydroxyphenyl)retinamide induced autophagy at a lower dose enhances cell death in malignant glioma cells
1 Department of Endocrinology, Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226 0140
2 Electron Microscopy Unit, Central Drug Research Institute, Mahatma Gandhi Marg, Lucknow, 226 001 India
* To whom correspondence should be addressed, Professor Madan M. Godbole, Department of Endocrinology, SGPGIMS, Raebareli Road, Lucknow 226 014 India. Phone: +91-522-2668700, Extension: 2368 Fax: +91-522-2668017, E-mail: madangodbole{at}yahoo.co.in
The question whether chemotherapy induced autophagy is causative to the demise of the cells or is it a part of the survival mechanism activated during cellular distress is unclear. Others and we have previously demonstrated apoptosis inducing capacity of N-(4-hydroxyphenyl) retinamide (4-HPR) in malignant glioma cells. We provide evidences of 4-HPR induced autophagy at a lower concentration (5 µM). Sub optimal dose of 4-HPR treatment of malignant gliomas cell lines increased G2/M arrest whereas cell accumulated in S-phase at a higher concentration. 4-HPR-induced autophagy was associated with acidic vacuole (AVO) formation and recruitment of microtubule-associated protein light chain 3 (LC3). At higher concentration of 10 µM of 4-HPR glioma cells undergoing apoptosis manifested autophagic features indicated by autophagosome formation, AVO development and LC3 localization. Autophagy inhibition at an early stage by 3-methyladenine inhibited the AVO formation and LC3 localization with an enhancement in cell death. Bafilomycin A1, a specific inhibitor of vacuolar type Hþ-ATPase also prevented AVO formation without effecting LC-3 localization pattern and also enhanced the extent of 4-HPR-induced cell death. 4-HPR activated c-jun and P38MAPK at both 5 µM and 10 µM concentrations, where as increased activation of ERK1/2 and NF-kB was seen only at lower dose. Inhibiting PI3K and MAPK's pathways modulated 4-HPR-induced cell death. This is the first report that provides evidences that besides apoptosis induction 4-HPR can also induce autophagy. These results indicate that 4-HPR-induced autophagy in glioma cell may provide survival advantage and inhibition of autophagy may enhance the cytotoxicity to 4-HPR.
Key Words: Glioma • 4-HPR • Autophagy • Apoptosis
Received May 25, 2007; revised October 30, 2007; accepted October 30, 2007.
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