Poonam Gupta1, Pratibha Singh1, Hriday S Pandey2, Pankaj Seth2, Chinmay K Mukhopadhyay3. 1. Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India. 2. National Brain Research Centre, Manesar, Haryana, India. 3. National Brain Research Centre, Manesar, Haryana, India. Electronic address: ckm2300@mail.jnu.ac.in.
Abstract
BACKGROUND: Elevated endogenous phosphoinositide-3-kinase (PI3K) activity is critical for cell proliferation in gliomas. Iron availability is one of the essential factors for cell growth and proliferation. However, any relation between PI3K and cellular iron homeostasis has not been understood so far. METHODS: Glioma cells and human primary astrocytes were treated with class I PI3K inhibitors to examine regulation of iron homeostasis components. Regulation of ferritin was detected at mRNA and translational level. Labile iron pool (LIP) and cell proliferation were examined in glioma cells and human primary astrocytes. RESULTS: Blocking of PI3K activity elevated ferritin level by 6-10 folds in glioma cells by augmenting mRNA expression of ferritin subunits and also by influencing ferritin translation. IRE-IRP interaction was affected due to conversion of IRP1 to cytosolic aconitase that was influenced by increased iron-sulfur scaffold protein iron-sulfur cluster assembly enzyme (ISCU) level. Elevated ferritin sequestered LIP to affect cell proliferation that was reversed in silencing ferritin by siRNAs of ferritin-H and ISCU. Human primary astrocyte with little PI3K activity did not show any change in ferritin level, LIP and cell proliferation by PI3K inhibitors. CONCLUSIONS: PI3K inhibition promotes ferritin synthesis by dual mechanism resulting sequestration of iron to limit its availability for cell proliferation in glioma cells but not in primary astrocytes. GENERAL SIGNIFICANCE: This observation establishes a relation between PI3K signalling and iron homeostasis in glioma cells. It also implies that activated PI3K controls ferritin expression to ensure availability of adequate iron required for cell proliferation.
BACKGROUND: Elevated endogenous phosphoinositide-3-kinase (PI3K) activity is critical for cell proliferation in gliomas. Iron availability is one of the essential factors for cell growth and proliferation. However, any relation between PI3K and cellular iron homeostasis has not been understood so far. METHODS:Glioma cells and human primary astrocytes were treated with class I PI3K inhibitors to examine regulation of iron homeostasis components. Regulation of ferritin was detected at mRNA and translational level. Labile iron pool (LIP) and cell proliferation were examined in glioma cells and human primary astrocytes. RESULTS: Blocking of PI3K activity elevated ferritin level by 6-10 folds in glioma cells by augmenting mRNA expression of ferritin subunits and also by influencing ferritin translation. IRE-IRP interaction was affected due to conversion of IRP1 to cytosolic aconitase that was influenced by increased iron-sulfur scaffold protein iron-sulfur cluster assembly enzyme (ISCU) level. Elevated ferritin sequestered LIP to affect cell proliferation that was reversed in silencing ferritin by siRNAs of ferritin-H and ISCU. Human primary astrocyte with little PI3K activity did not show any change in ferritin level, LIP and cell proliferation by PI3K inhibitors. CONCLUSIONS: PI3K inhibition promotes ferritin synthesis by dual mechanism resulting sequestration of iron to limit its availability for cell proliferation in glioma cells but not in primary astrocytes. GENERAL SIGNIFICANCE: This observation establishes a relation between PI3K signalling and iron homeostasis in glioma cells. It also implies that activated PI3K controls ferritin expression to ensure availability of adequate iron required for cell proliferation.
Authors: Kobra Alizadeh; Qin Sun; Tabitha McGuire; Terry Thompson; Frank S Prato; Jim Koropatnick; Neil Gelman; Donna E Goldhawk Journal: Sci Rep Date: 2020-02-21 Impact factor: 4.379