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

Yingqiu Xie, Kexin Xu, Douglas E. Linn, Xi Yang, Zhiyong Guo, Hermela Shimelis, Takeo Nakanishi, Douglas D. Ross, Hegang Chen, Ladan Fazli, Martin E. Gleave, Yun Qiu

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127 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3349-3356
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number6
DOIs
StatePublished - Feb 8 2008
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Xie, Y., Xu, K., Linn, D. E., Yang, X., Guo, Z., Shimelis, H., Nakanishi, T., Ross, D. D., Chen, H., Fazli, L., Gleave, M. E., & Qiu, Y. (2008). The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells. Journal of Biological Chemistry, 283(6), 3349-3356. https://doi.org/10.1074/jbc.M707773200