title: Aluminium induced endoplasmic reticulum stress mediated cell death in SH-SY5Y neuroblastoma cell line is independent of p53.
abstract: Aluminium (Al) is the third most abundant element in the earth's crust and its compounds are used in the form of house hold utensils, medicines and in antiperspirant etc. Increasing number of evidences suggest the involvement of Al+3 ions in a variety of neurodegenerative disorders including Alzheimer's disease. Here, we have attempted to investigate the role of Al in endoplasmic reticulum stress and the regulation of p53 during neuronal apoptosis using neuroblastoma cell line. We observed that Al caused oxidative stress by increasing ROS production and intracellular calcium levels together with depletion of intracellular GSH levels. We also studied modulation of key pro- and anti-apoptotic proteins and found significant alterations in the levels of Nrf2, NQO1, pAKT, p21, Bax, Bcl2, Aβ1-40 and Cyt c together with increase in endoplasmic reticulum (ER) stress related proteins like CHOP and caspase 12. However, with respect to the role of p53, we observed downregulation of its transcript as well as protein levels while analysis of its ubiquitination status revealed no significant changes. Not only did Al increase the activities of caspase 9, caspase 12 and caspase 3, but, by the use of peptide inhibitors of specific and pan-caspases, we observed significant protection against neuronal cell death upon inhibition of caspase 12, demonstrating the prominent role of endoplasmic reticulum stress generated responses in Al toxicity. Overall our findings suggest that Al induces ER stress and ROS generation which compromises the antioxidant defenses of neuronal cells thereby promoting neuronal apoptosis in p53 independent pathway.
authors.affiliation: Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India.
authors.forename: Syed Husain
authors.initials: SH
authors.lastname: Mustafa Rizvi
authors.affiliation: Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India.
authors.forename: Arshiya
authors.initials: A
authors.lastname: Parveen
authors.affiliation: Forensic Medicine & Toxicology, King George's Medical University, Lucknow, Uttar Pradesh, India.
authors.forename: Anoop K
authors.initials: AK
authors.lastname: Verma
authors.affiliation: Fibre Toxicology Division, CSIR- Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Department of Zoology, Lucknow University, Lucknow, Uttar Pradesh, India.
authors.forename: Md
authors.initials: M
authors.lastname: Arshad
authors.affiliation: Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India.
authors.forename: Abbas Ali
authors.initials: AA
authors.lastname: Mahdi
mesh_terms: D000535:Aluminum / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D020169:Caspases / Q000235:genetics; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051742:Transcription Factor CHOP; D000535:Aluminum; D020169:Caspases