Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(3):600-609; 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
Department of Endocrinology
1 Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India
2 Electron Microscopy Unit, 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
The question whether chemotherapy-induced autophagy is causative to the demise of the cells or 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). Suboptimal dose of 4-HPR treatment of malignant glioma 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 [acidic vesicular organelle (AVO)] formation and recruitment of microtubule-associated protein light chain 3 (LC3). At a 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-methyl adenine 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 and 10 µM concentrations, whereas increased activation of extracellular signal-regulated kinase 1/2 and NF-kappaB was seen only at lower dose. Inhibiting phosphoinositide 3-kinase and mitogen-activated protein kinases 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.
Abbreviations: AO, acridine orange; AVO, acidic vesicular organelle; Baf-A1, bafilomycin A1; CMFDA, 5-chloromethylfluoresceine diacetate; DCF-DA, 2',7'-dichlorofluorescine diacetate; DMSO, dimethyl sulfoxide; ERK, extracellular signal-regulated kinase; 4-HPR, N-(4-hydroxyphenyl)retinamide; JC-1, 5,5',6,6'-tetrachlo-1-1',3,3'tetraethylbenzimidazolylcarbocyanine iodide; JNK, c-jun N-terminal kinase; LC3, light chain 3; LTR, Lysotracker red; 3-MA, 3-methyl adenine; MAPK, mitogen-activated protein kinase; NF-
B, NF-kappaB; PBS, phosphate-buffered saline; PI, propidium iodide; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species
Received May 25, 2007; revised October 30, 2007; accepted October 30, 2007.
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