The relationship of thioredoxin-1 and cisplatin resistance

Its impact on ROS and oxidative metabolism in lung cancer cells

Medhi Wangpaichitr, Elizabeth J. Sullivan, George Theodoropoulos, Chunjing Wu, Min You, Lynn G Feun, Theodore Lampidis, Macus T. Kuo, Niramol Savaraj

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Elimination of cisplatin-resistant lung cancer cells remains a major obstacle. We have shown that cisplatin-resistant tumors have higher reactive oxygen species (ROS) levels and can be exploited for targeted therapy. Here, we show that increased secretion of the antioxidant thioredoxin-1 (TRX1) resulted in lowered intracellular TRX1 and contributed to higher ROS in cisplatin-resistant tumors in vivo and in vitro. By reconstituting TRX1 protein in cisplatin-resistant cells, we increased sensitivity to cisplatin but decreased sensitivity to elesclomol (ROS inducer). Conversely, decreased TRX1 protein in parental cells reduced the sensitivity to cisplatin but increased sensitivity to elesclomol. Cisplatin-resistant cells had increased endogenous oxygen consumption and mitochondrial activity but decreased lactic acid production. They also exhibited higher levels of argininosuccinate synthetase (ASS) and fumarasem RNA,which contributed to oxidative metabolism (OXMET) when compared with parental cells. Restoring intracellular TRX1 protein in cisplatin-resistant cells resulted in lowering ASS and fumarase mRNAs, which in turn sensitized them to arginine deprivation. Interestingly, cisplatin-resistant cells also had significantly higher basal levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Overexpressing TRX1 lowered ACC and FAS proteins expressions in cisplatin-resistant cells. Chemical inhibition and short interfering RNA of ACC resulted in significant cell death in cisplatin-resistant compared with parental cells. Conversely,TRX1 overexpressed cisplatin-resistant cells resisted5-(tetradecyloxy)-2-furoic acid (TOFA)-induced death.Collectively, lowering TRX1 expression through increased secretion leads cisplatin-resistant cells to higher ROS production and increased dependency on OXMET. These changes raise an intriguing therapeutic potential for future therapy in cisplatin-resistant lung cancer.

Original languageEnglish
Pages (from-to)604-615
Number of pages12
JournalMolecular Cancer Therapeutics
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2012

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Thioredoxins
Cisplatin
Reactive Oxygen Species
Lung Neoplasms
Acetyl-CoA Carboxylase
Argininosuccinate Synthase
Fatty Acid Synthases
Proteins
Fumarate Hydratase
Oxygen Consumption
Small Interfering RNA
Arginine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The relationship of thioredoxin-1 and cisplatin resistance : Its impact on ROS and oxidative metabolism in lung cancer cells. / Wangpaichitr, Medhi; Sullivan, Elizabeth J.; Theodoropoulos, George; Wu, Chunjing; You, Min; Feun, Lynn G; Lampidis, Theodore; Kuo, Macus T.; Savaraj, Niramol.

In: Molecular Cancer Therapeutics, Vol. 11, No. 3, 01.03.2012, p. 604-615.

Research output: Contribution to journalArticle

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