title: Inhibition of N-(4-hydroxyphenyl)retinamide-induced autophagy at a lower dose enhances cell death in malignant glioma cells.
abstract: 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 microM). Suboptimal dose of 4-HPR treatment of malignant glioma cell lines increased G(2)/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 microM 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 Hthorn-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 P38(MAPK) at both 5 and 10 microM 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.
authors.affiliation: Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Tiwari
authors.forename: Virendra Kumar
authors.initials: VK
authors.lastname: Bajpai
authors.forename: Amogh Anant
authors.initials: AA
authors.lastname: Sahasrabuddhe
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Rohit Anthony
authors.initials: RA
authors.lastname: Sinha
authors.forename: Sanjay
authors.initials: S
authors.lastname: Behari
authors.forename: Madan Madhav
authors.initials: MM
authors.lastname: Godbole
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D001932:Brain Neoplasms / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D017313:Fenretinide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005434:Flow Cytometry; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D046529:Microscopy, Electron, Transmission; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D017313:Fenretinide; D011494:Protein Kinases