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Original Article

Cytoplasmic Confinement of Breast Cancer Resistance Protein (BCRP/ABCG2) as a Novel Mechanism of Adaptation to Short-Term Folate Deprivation

Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel (I.I., Y.G.A.); and Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands (G.J.)

Abstract

The unique capability of breast cancer resistance protein (BCRP/ABCG2) to export mono-, di-, and triglutamates of folates should limit cellular proliferation under conditions of folate deprivation, particularly upon BCRP overexpression. Here, we explored the mode of adaptation of BCRP-overexpressing cells to short-term folate deprivation. MCF-7/MR cells grown in high folate medium (2.3 µM folic acid) containing mitoxantrone had 62% of their overexpressed BCRP in the plasma membrane and only 38% in the cytoplasm. In contrast, cells grown for 2 weeks in folic acid-free medium followed by an adaptation week in low folate medium (1 nM folic acid) had 86% of BCRP in the cytoplasm and only 14% in the plasma membrane. Unlike BCRP, various transmembrane proteins retained their normal plasma membrane localization in folate-deprived cells. Folate deprivation was also associated with a 3-fold decrease in BCRP and multidrug resistance protein 1 (MRP1/ABCC1) levels. Confocal microscopy with folate-deprived cells revealed that cytoplasmic BCRP colocalized with calnexin, an established endoplasmic reticulum resident. The loss of BCRP from the plasma membrane in folate-deprived cells consistently resulted in a 4.5-fold increase in [³H]folic acid accumulation relative to MCF-7/MR cells. Hence, cellular adaptation to shortterm folate deprivation results in a selective confinement of BCRP to the cytoplasm along with a moderate decrease in BCRP and MRP1 levels aimed at preserving the poor intracellular folate pools. These results constitute a novel mechanism of cellular adaptation to short-term folate deprivation and provide further support to the possible role of BCRP in the maintenance of cellular folate homeostasis.

Address correspondence to: Dr. Yehuda G. Assaraf, Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel. E-mail: assaraf{at}tx.technion.ac.il

This article has been cited by other articles:

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