2. Academic Validation
  3. The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells

The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells

  • J Biol Chem. 2008 Feb 8;283(6):3349-3356. doi: 10.1074/jbc.M707773200.
Yingqiu Xie 1,  Kexin Xu 1,  Douglas E Linn 1,  Xi Yang 1,  Zhiyong Guo 1,  Hermela Shimelis 1,  Takeo Nakanishi 2,  Douglas D Ross 3,  Hegang Chen 4,  Ladan Fazli 5,  Martin E Gleave 5,  Yun Qiu 6
Affiliations

Affiliations

  • 1 Departments of Pharmacology and Experimental Therapeutics.
  • 2 Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201; The Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201.
  • 3 Departments of Pharmacology and Experimental Therapeutics; Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201; The Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201; Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201; The Baltimore Veterans Affair Medical Center, Baltimore, Maryland 21201.
  • 4 Epidemiology & Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201.
  • 5 The Prostate Center, Vancouver General Hospital, Vancouver, British Columbia V6H 3Z6, Canada.
  • 6 Departments of Pharmacology and Experimental Therapeutics; The Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201. Electronic address: yqiu@som.umaryland.edu.
PMID: 18056989 DOI: 10.1074/jbc.M707773200
Abstract

We previously showed that the 44-kDa serine/threonine kinase Pim-1 (Pim-1L) can protect prostate Cancer cells from Apoptosis induced by chemotherapeutic drugs (Xie, Y., Xu, K., Dai, B., Guo, Z., Jiang, T., Chen, H., and Qiu, Y. (2006) Oncogene 25, 70-78). To further explore the mechanisms of Pim-1L-mediated resistance to chemotherapeutic drugs in prostate Cancer cells, we employed a yeast two-hybrid screening to identify cellular proteins that were associated with Pim-1L, and we found the ABC transporter BCRP/ABCG2 as one of the potential interacting partners of Pim-1L. We also showed that the expression level of Pim-1L and BCRP was up-regulated in mitoxantrone and docetaxel-resistant prostate Cancer cell lines. Pim-1L was co-localized with BCRP on the plasma membrane and induced phosphorylation of BCRP at threonine 362. Knocking-down Pim-1L expression in the drug-resistant prostate Cancer cells abolished multimer formation of endogenous BCRP and resensitized the resistant cells to chemotherapeutic drugs suggesting that BCRP phosphorylation induced by Pim-1L was essential for its functionality. This is further corroborated by our finding that the plasma membrane localization and drug-resistant activity of BCRP were compromised by T362A mutation. Our data suggest that Pim-1L may protect prostate Cancer cells from Apoptosis, at least in part, through regulation of transmembrane drug efflux pump. These findings may provide a potential therapeutic approach by disrupting Pim-1 signaling to reverse BCRP-mediated multidrug resistance.

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