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

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.

• Authors: 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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 6 Pg. 3349-3356 (Feb 08 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18056989 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Neoplasm Proteins
• Threonine

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (biosynthesis, physiology)
• Amino Acid Sequence
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Molecular Sequence Data
• Neoplasm Proteins (biosynthesis, physiology)
• Phosphorylation
• Prostatic Neoplasms (drug therapy, metabolism)
• Protein Structure, Tertiary
• Sequence Homology, Amino Acid
• Threonine (chemistry)
• Two-Hybrid System Techniques