Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells

We described an interplay between mitochondrial-derived oxidants and expression of FOXM1, a redox-responsive transcription factor that has emerged as a promising therapeutic target in solid malignancies

Brian Cunniff; Kira Benson; Jason Stumpff; Kheng Newick; Paul Held; Douglas Taatjes; Joy Joseph; Balaraman Kalyanaraman; Nicholas H. Heintz

2012

Scholarcy highlights

  • Malignant mesothelioma is an intractable tumor of the peritoneal and pleural cavities primarily linked to exposure to asbestos
  • An inhibitor of complex I of the electron transport chain, we examined the relationship between mitochondrial superoxide production and FOXM1 expression in LP9 cells and MM HM cells
  • These results suggest that expression of FOXM1 is tuned to the production of cellular oxidants that include mitochondrial superoxide and hydrogen peroxide or oxidants formed there from, but that tumor cells function closer to a threshold of oxidant production that inhibits FOXM1 expression
  • In cancer cells mitochondria do not appear defective in many aspects of energy metabolism, but rather respond to deregulation of the cell cycle and other signaling pathways by exploiting aerobic glycolysis for production of reducing equivalents required for biosynthetic processes and cell cycle progression
  • As in other tumor types, we have described an increase in the oxidative state of MM cell mitochondria that is accompanied by an adaptive response of up-regulation of a primary mitochondrial antioxidant network composed of thioredoxin reductase 2-thioredoxin 2-peroxiredoxin 3, which is responsible for 90% of the metabolism of mitochondrial H2O2
  • Our previous findings have demonstrated that targeting of the mitochondrial antioxidant network with the TRX2 inhibitor gentian violet or the thiazole antibiotic thiostrepton leads to intolerable levels of mitochondrial oxidants, loss of FOXM1 expression, and MM cell death
  • While several compounds over time increase the relative levels of mitochondrial oxidants, the results with peroxiredoxin 3 indicate it is unlikely that a common mechanism is responsible for inhibition of FOXM1 by each agent

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