TNFalpha induced oxidative stress dependent Akt signaling affects actin cytoskeletal organization in glioma cells

Neurochem Int. 2010 Jan;56(1):194-201. doi: 10.1016/j.neuint.2009.10.003. Epub 2009 Oct 25.

Abstract

Inflammation which is an indispensable participant in tumor progression is intricately linked with redox modulation. The pro-inflammatory cytokine Tumor Necrosis Factor (TNFalpha) elevates reactive oxygen species (ROS) in glioblastoma multiforme (GBM). As both TNFalpha and oxidative stress independently play role in regulating cytoskeletal organization and cell survival pathways we investigated whether TNFalpha mediated oxidative stress regulates responses that offer survival advantages to glioblastoma cells. Treatment with TNFalpha elevated Akt phosphorylation in glioma cells. Increased in Akt phosphorylation was concurrent with the decrease in ROS scavenger SOD-1 levels. TNFalpha mediated increase in Akt phosphorylation was dependent on oxidative stress as Akt phosphorylation was abrogated in the presence of ROS inhibitor and elevated in cells transfected with SOD-1 siRNA. TNFalpha altered actin cytoskeletal organization and increased Cdc42 levels. This increase in Cdc42 was concomitant with its increased interaction with scaffold protein IQGAP-1. Also, we report for the first time a ROS dependent interaction between pAkt and IQGAP-1 in TNFalpha treated cells. Importantly, Akt inhibition not only reversed TNFalpha mediated changes in actin cytoskeletal organization but also abrogated anchorage independent growth. Together, these results suggest that TNFalpha induced oxidative stress affects Akt activation to regulate actin organization and growth of glioma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / metabolism*
  • Actin Cytoskeleton / pathology
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / physiopathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Cytoskeleton / pathology
  • Encephalitis / etiology
  • Encephalitis / metabolism
  • Encephalitis / physiopathology
  • Enzyme Inhibitors / pharmacology
  • Glioma / drug therapy
  • Glioma / metabolism*
  • Glioma / physiopathology
  • Humans
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Superoxide Dismutase / drug effects
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • cdc42 GTP-Binding Protein / drug effects
  • cdc42 GTP-Binding Protein / metabolism
  • ras GTPase-Activating Proteins / drug effects
  • ras GTPase-Activating Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • IQ motif containing GTPase activating protein 1
  • Reactive Oxygen Species
  • SOD1 protein, human
  • Tumor Necrosis Factor-alpha
  • ras GTPase-Activating Proteins
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Proto-Oncogene Proteins c-akt
  • cdc42 GTP-Binding Protein