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High levels of thioredoxin reductase 1 modulate drug-specific cytotoxic efficacy

Sofi E Eriksson1, Stefanie Prast-Nielsen, Emilie Flaberg

  • 1Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

Free Radical Biology & Medicine
|September 22, 2009
PubMed

Insights

Targeting thioredoxin reductase 1 (TrxR1) in lung cancer cells impacts chemotherapy response. TrxR1 knockdown altered sensitivity to certain drugs, suggesting a role beyond thioredoxin function in cancer treatment.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Thioredoxin reductase 1 (TrxR1) is a key selenoprotein and a potential anticancer target.
  • A549 lung carcinoma cells exhibit high basal TrxR1 expression, making them a suitable model for studying TrxR1 function.

Purpose of the Study:

  • To investigate the effects of TrxR1 targeting on lung carcinoma cell growth and response to chemotherapy.
  • To determine if TrxR1's role in drug sensitivity is solely linked to its thioredoxin reductase activity.

Main Methods:

  • Utilized siRNA to achieve approximately 90% knockdown of TrxR1 in A549 cells.
  • Assessed cellular TrxR activity, thioredoxin activity, cell growth, cell death, cell cycle distribution, and sensitivity to various chemotherapeutic agents.
  • Investigated the impact of concurrent glutathione depletion on TrxR1 knockdown effects.

Main Results:

  • TrxR1 knockdown had minimal impact on cell growth, death, or cell cycle, even with significant glutathione depletion.
  • Sensitivity to 1-chloro-2,4-dinitrobenzene and menadione increased after TrxR1 knockdown.
  • Resistance to cisplatin developed upon TrxR1 knockdown, while responses to auranofin and juglone remained unchanged.
  • Cellular TrxR activity significantly exceeded thioredoxin activity in A549 cells.

Conclusions:

  • High TrxR1 expression influences drug-specific cytotoxic responses independently of its direct thioredoxin reductase function.
  • TrxR1 targeting presents a complex modulation of chemotherapy efficacy, highlighting its potential as an anticancer drug target with nuanced effects.

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