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Hyperglycemia-Induced Thioredoxin-Interacting Protein Expression Differs in Breast Cancer–Derived Cells and Regulates Paclitaxel IC₅₀

Authors' Affiliations: ¹ Department of Medicine, Feist-Weiller Cancer Center and ² Gene Therapy Program, Louisiana State University Health Science Center, Shreveport, Louisiana

Requests for reprints: Francesco Turturro, Department of Medicine, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71103. Phone: 318-675-8863; Fax: 318-675-4338; E-mail: fturtu{at}lsuhsc.edu.

Purpose: We studied the hyperglycemia-induced expression of thioredoxin-interacting protein (TXNIP) expression and its relevance on the cytotoxic activity of paclitaxel in mammary epithelial–derived cell lines.

Experimental Design: Nontumorigenic cells (MCF10A); tumorigenic, nonmetastatic cells (MCF-7/T47D); and tumorigenic, metastatic cells (MDA-MB-231/MDA-MB-435s) were grown either in 5 or 20 mmol/L glucose chronically. Semiquantitative reverse transcription-PCR was used to assess TXNIP RNA expression in response to glucose. Reactive oxygen species were detected by CM-H2DCFDA (5-6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate) and measured for mean fluorescence intensity with flow cytometry. Thioredoxin activity was assayed by the insulin disulfide-reducing assay. Proliferation was evaluated using CellTiter96 reagent with 490-nm absorption. Obtained absorbance values were used to calculate the paclitaxel IC₅₀ in 5 or 20 mmol/L glucose using the Chou's dose-effect equation.

Results: We show that hyperglycemia by itself affects the level of TXNIP RNA in breast cancer–derived cells. TXNIP RNA level differs between nontumorigenic/nonmetastatic, tumorigenic cells (low TXNIP level), and metastatic cells (high TXNIP level). The differences in TXNIP RNA level, in reactive oxygen species level, and in thioredoxin activity are all related. We further show that hyperglycemia is a favorable condition in increasing the paclitaxel cytotoxicity by causing IC₅₀ 3-fold decrease in metastatic breast cancer–derived MDA-MB-231 cells. The increased paclitaxel cytotoxicity is associated with an additive effect on the hyperglycemia-mediated TXNIP expression more evident in conditions of hyperglycemia than normoglycemia.

Conclusions: Our study opens a new perspective on the relevance of metabolic conditions of hyperglycemia in the biology and treatment of cancer, particularly in view of the epidemic of diabetes.