The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells.
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.
Xie
Yingqiu
Y
Departments of Pharmacology and Experimental Therapeutics.
Xu
Kexin
K
Departments of Pharmacology and Experimental Therapeutics.
Linn
Douglas E
DE
Departments of Pharmacology and Experimental Therapeutics.
Yang
Xi
X
Departments of Pharmacology and Experimental Therapeutics.
Guo
Zhiyong
Z
Departments of Pharmacology and Experimental Therapeutics.
Shimelis
Hermela
H
Departments of Pharmacology and Experimental Therapeutics.
Nakanishi
Takeo
T
Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201; The Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201.
Ross
Douglas D
DD
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.
Chen
Hegang
H
Epidemiology & Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201.
Fazli
Ladan
L
The Prostate Center, Vancouver General Hospital, Vancouver, British Columbia V6H 3Z6, Canada.
Gleave
Martin E
ME
The Prostate Center, Vancouver General Hospital, Vancouver, British Columbia V6H 3Z6, Canada.
Qiu
Yun
Y
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.
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000502:physiology*; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000502:physiology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013912:Threonine / Q000737:chemistry; D020798:Two-Hybrid System Techniques
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D013912:Threonine