The redox state of the lung cancer microenvironment depends on the levels of thioredoxin expressed by tumor cells and affects tumor progression and response to prooxidants

Jenny Ceccarelli, Laura Delfino, Emanuela Zappia, Patrizia Castellani, Martina Borghi, Silvano Ferrini, Francesca Tosetti, Anna Rubartelli

Research output: Contribution to journalArticle

Abstract

Here we report that human nonsmall cell lung carcinomas overexpress macrophage migration inhibitory factor (MIF) and thioredoxin (Trx), 2 oxidoreductases with cytokine function, and contain more abundant nonprotein thiols (glutathione and cysteine) than nonneoplastic lung tissues. Cell clones derived from the same lung carcinoma cell lines but expressing different levels of Trx and/or MIF displayed growth rates in vitro and in vivo correlating with Trx but not with MIF. Interestingly, the different clones generate extracellularly reduced nonprotein thiols, in amounts related to the Trx content and inhibited by inhibitors of Trx function. Each clone also showed distinct responses to the prooxidant compound arsenic trioxide. Cells with a strongly antioxidant and aggressive phenotype were more susceptible to the cytotoxic effect of the drug than cells expressing little Trx. The latter counteracted the oxidative stress by increasing Trx expression and thiol release. Together these results indicate that different human lung cancer cell lines have distinct redox properties defined by the levels of Trx and nonprotein thiols, the higher antioxidant phenotype correlating with the higher aggressiveness. Moreover, the redox phenotype dictates their response to prooxidant drugs and must be taken into account when therapeutic interventions with redox active substances are considered.

Original languageEnglish
Pages (from-to)1770-1778
Number of pages9
JournalInternational Journal of Cancer
Volume123
Issue number8
DOIs
Publication statusPublished - Oct 15 2008

Keywords

  • Arsenic trioxide
  • MIF
  • Non protein thiols
  • Reduction/oxidation
  • Thioredoxin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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