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Transcriptional regulation, stabilization, and subcellular redistribution of multidrug resistance-associated protein 1 (MRP1) by glycogen synthase kinase 3αβ: novel insights on modes of cadmium-induced cell death stimulated by MRP1

  • Inorganic Compounds
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An Erratum to this article was published on 29 January 2015

Abstract

Cadmium (Cd) resistance is associated with the suppression of autophagy in H460 lung cancer cells, which is regulated by phospho(p)serine-glycogen synthase kinase (GSK) 3αβ. However, the involvement of multidrug resistance (MDR) in this signaling pathway and its underlying mechanisms remain to be elucidated. In this study, we used Cd-resistant cells (RH460), developed from H460 lung cancer cells, to demonstrate that the induction of MDR-associated protein (MRP1) in response to Cd is enhanced in H460 cells compared to RH460. Treating RH460 cells with Cd induced large cytoplasmic vacuoles, which was inhibited by the autophagy inhibitor 3-methyladenine. MRP1 was detected in the nuclear-rich membrane fractions and redistributed from the perinuclear to the cytoplasmic compartment following exposure to Cd. Cd-induced MRP1, p-Ser/p-Tyr GSK3αβ, and LC3-II were all suppressed by the GSK3 inhibitor SB216763, but increased by lithium. Furthermore, MRP1 was upregulated by the Ser/Thr phosphatase inhibitor okadaic acid and downregulated by the tyrosine phosphatase inhibitor vanadate, suggesting that MRP1 protein was stabilized by p-Ser GSK3αβ. In addition, co-immunoprecipitation and co-localization analyzes revealed a physical interaction between MRP1 and p-Ser GSK3αβ. Genetic knockdown of GSK3β decreased Cd-induced MRP1 mRNA and protein levels, whereas its overexpression upregulated MRP1 protein expression. MRP1 also co-localized with lysosomal membrane protein-2, which may cause lysosomal membrane permeabilization and the subsequent release of cathepsins into the cytosol. In mice chronically injected with Cd, MRP1 localized to the perinuclear region of bronchial and alveolar epithelial cells. Collectively, these data suggest that Cd toxicity is regulated by the transcriptional regulation, stabilization, and subcellular redistribution of MRP1 via the posttranslational modification of GSK3αβ. Therefore, the serine phosphorylation of GSK3αβ plays a critical role in MRP1-induced cell death.

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0014070) and the Ministry of Science, ICT & Future Planning (R13-2008-010-00000-0).

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Authors and Affiliations

  1. Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, 570-749, Korea

    Hak-Ryul Kim

  2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Korea

    Kang-Yoo Lee & Byung-Hoon Lee

  3. Department of Pathology, College of Dentistry, Chosun University, Gwangju, 501-759, Korea

    Sang-Gun Ahn & Hyo-Eun Yoon

  4. Department of Anesthesiology and Pain Medicine, School of Medicine, Chosun University, Gwangju, 501-759, Korea

    Ki-Tae Jung

  5. Department of Oral and Maxillofacial Pathology, Daejeon Dental Hospital, College of Dentistry, Wonkwang Bone Regeneration Research Institute, Wonkwang University, Daejeon, 302-120, Korea

    Jung-Hoon Yoon

  6. The Division of Natural Medical Sciences, College of Health Science, Chosun University, Seosuk-dong, Dong-gu, Gwangju, 501-759, Korea

    Seon-Hee Oh

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  1. Hak-Ryul Kim
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Correspondence to Seon-Hee Oh.

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Hak-Ryul Kim and Kang-Yoo Lee have contributed equally to the work.

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Kim, HR., Lee, KY., Ahn, SG. et al. Transcriptional regulation, stabilization, and subcellular redistribution of multidrug resistance-associated protein 1 (MRP1) by glycogen synthase kinase 3αβ: novel insights on modes of cadmium-induced cell death stimulated by MRP1. Arch Toxicol 89, 1271–1284 (2015). https://doi.org/10.1007/s00204-014-1381-9

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