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. 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. The proto-oncogene pim-1 encodes two serine/threonine kinases with molecular masses of 33 and 44 kDa by utilizing two alternative translation sites (1Saris C.J. Domen J. Berns A. EMBO J. 1991; 10: 655-664Crossref PubMed Scopus (265) Google Scholar, 2Xie Y. Xu K. Dai B. Guo Z. Jiang T. Chen H. Qiu Y. Oncogene. 2006; 25: 70-78Crossref PubMed Scopus (101) Google Scholar). These two Pim-1 proteins exhibit comparable in vitro kinase activity. However, the 44-kDa Pim-1 appears to be more stable (1Saris C.J. Domen J. Berns A. EMBO J. 1991; 10: 655-664Crossref PubMed Scopus (265) Google Scholar). Studies have shown that the 33-kDa Pim-1 is monomeric in vivo, whereas the 44-kDa Pim-1 is found in a complex (1Saris C.J. Domen J. Berns A. EMBO J. 1991; 10: 655-664Crossref PubMed Scopus (265) Google Scholar), suggesting the latter may interact with more protein partners. Our current knowledge on Pim-1 kinases is largely derived from study on the 33-kDa isoform. The 33-kDa Pim-1 has been implicated in the regulation of cell cycle and transcription by phosphorylating a number of substrates such as cdc25A, HP1, and p100 (3Koike N. Maita H. Taira T. Ariga H. Iguchi-Ariga S.M. FEBS Lett. 2000; 467: 17-21Crossref PubMed Scopus (98) Google Scholar, 4Mochizuki T. Kitanaka C. Noguchi K. Muramatsu T. Asai A. Kuchino Y. J. Biol. Chem. 1999; 274: 18659-18666Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 5Xie X. Zhao X. Liu Y. Zhang J. Matusik R.J. Slawin K.M. Spencer D.M. Cancer Res. 2001; 61: 6795-6804PubMed Google Scholar, 6Leverson J.D. Koskinen P.J. Orrico F.C. Rainio E.M. Jalkanen K.J. Dash A.B. Eisenman R.N. Ness S.A. Mol. Cell. 1998; 2: 417-425Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). Moreover, it has been shown that Pim-1 may play a role in the regulation of the survival signaling by phosphorylating BAD (7Macdonald A. Campbell D.G. Toth R. McLauchlan H. Hastie C.J. Arthur J.S. BMC Cell Biol. 2006; 7: 1Crossref PubMed Scopus (147) Google Scholar). Pim-1 is thought to play an integral role in the development of a number of human cancers, such as hematolymphoid malignancies (8Bachmann M. Kosan C. Xing P.X. Montenarh M. Hoffmann I. Moroy T. Int. J. Biochem. Cell Biol. 2006; 38: 430-443Crossref PubMed Scopus (109) Google Scholar, 9Allen J.D. Schinkel A.H. Mol. Cancer Ther. 2002; 1: 427-434Crossref PubMed Google Scholar). A number of studies demonstrated that Pim-1 is up-regulated in both human prostate cancer as well as animal models and may play an important role in prostate cancer development and progression (10Dhanasekaran S.M. Barrette T.R. Ghosh D. Shah R. Varambally S. Kurachi K. Pienta K.J. Rubin M.A. Chinnaiyan A.M. Nature. 2001; 412: 822-826Crossref PubMed Scopus (1429) Google Scholar, 11Wang S. Gao J. Lei Q. Rozengurt N. Pritchard C. Jiao J. Thomas G.V. Li G. Roy-Burman P. Nelson P.S. Liu X. Wu H. Cancer Cell. 2003; 4: 209-221Abstract Full Text Full Text PDF PubMed Scopus (865) Google Scholar, 12Ellwood-Yen K. Graeber T.G. Wongvipat J. Iruela-Arispe M.L. Zhang J. Matusik R. Thomas G.V. Sawyers C.L. Cancer Cell. 2003; 4: 223-238Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar). Pim-1 has emerged as a potential diagnostic marker in prostate cancer (10Dhanasekaran S.M. Barrette T.R. Ghosh D. Shah R. Varambally S. Kurachi K. Pienta K.J. Rubin M.A. Chinnaiyan A.M. Nature. 2001; 412: 822-826Crossref PubMed Scopus (1429) Google Scholar). Recently, we have shown that the 44-kDa isoform Pim-1L may play a more prominent role in anti-apoptosis signaling in response to chemotherapeutic drugs in prostate cancer cells (2Xie Y. Xu K. Dai B. Guo Z. Jiang T. Chen H. Qiu Y. Oncogene. 2006; 25: 70-78Crossref PubMed Scopus (101) Google Scholar). The localization of the 44-kDa Pim-1L is primarily on the plasma membrane, and it contains an N-terminal proline-rich motif and interacts directly with tyrosine kinase Etk through an interaction between the PXXP motif and the SH3 domain of Etk. Such interaction competes with tumor suppressor p53 for binding to Etk and activates Etk kinase activity (13Jiang T. Guo Z. Dai B. Kang M. Ann D.K. Kung H.J. Qiu Y. J. Biol. Chem. 2004; 279: 50181-50189Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). Advanced metastatic prostate cancer treated by hormone manipulation or orchiectomy frequently leads to the development of progressive hormone-refractory prostate cancer and highly chemoresistant tumors. Several biochemical mechanisms of drug resistance have been identified in prostate cancer cell lines, including alterations of glutathione metabolism, altered topoisomerase activity, and up-regulation of the transmembrane drug efflux pumps (14Zalcberg J. Hu X.F. Slater A. Parisot J. El-Osta S. Kantharidis P. Chou S.T. Parkin J.D. Prostate Cancer Prostatic Dis. 2000; 3: 66-75Crossref PubMed Scopus (61) Google Scholar), and in particular ATP binding cassette (ABC) 3The abbreviations used are: ABCATP binding cassetteGSTglutathione S-transferaseHAhemagglutininMXmitoxantroneDTXdocetaxelPRproline-richTPTtoptecan. transporter family members such as multidrug resistance protein-1(MDR1/Pgp/ABCB1) and multidrug resistance-associated protein-1(MRP1/ABCC1). Recently it has been reported that MRP1 but not MDR1 overexpression contributes to acquired drug resistance in two prostate cancer cell lines derived from PC3 and DU145 (14Zalcberg J. Hu X.F. Slater A. Parisot J. El-Osta S. Kantharidis P. Chou S.T. Parkin J.D. Prostate Cancer Prostatic Dis. 2000; 3: 66-75Crossref PubMed Scopus (61) Google Scholar). It has been shown that the presence of a half ABC transporter, breast cancer resistance protein BCRP/ABCG2, isolates the putative prostate stem cells from the prostate tissue microenvironment through constitutive efflux of androgen and protects the putative tumor stem cells from androgen deprivation, hypoxia, or adjuvant chemotherapy, and provides the nidus for recurrent prostate cancer (15Huss W.J. Gray D.R. Greenberg N.M. Mohler J.L. Smith G.J. Cancer Res. 2005; 65: 6640-6650Crossref PubMed Scopus (107) Google Scholar). In addition to androgen, a large set of BCRP substrates has been identified including chemotherapeutic agents, fluorescent dyes, as well as chemical toxicants (16Doyle L.A. Ross D.D. Oncogene. 2003; 22: 7340-7358Crossref PubMed Scopus (922) Google Scholar). BCRP overexpression has been detected in a variety of mitoxantrone or other chemotherapeutic agents selected cell lines (17Janvilisri T. Venter H. Shahi S. Reuter G. Balakrishnan L. van Veen H.W. J. Biol. Chem. 2003; 278: 20645-20651Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 18Doyle L.A. Yang W. Abruzzo L.V. Krogmann T. Gao Y. Rishi A.K. Ross D.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15665-15670Crossref PubMed Scopus (1986) Google Scholar). The molecular mechanism of BCRP in drug efflux has been well studied in breast cancer cells. Several immunohistochemical studies using monoclonal and polyclonal antibodies have confirmed that BCRP is mainly localized to the plasma membrane of mammalian cells. Recent studies suggest that BCRP may function as a homodimer (19Kage K. Tsukahara S. Sugiyama T. Asada S. Ishikawa E. Tsuruo T. Sugimoto Y. Int. J. Cancer. 2002; 97: 626-630Crossref PubMed Scopus (268) Google Scholar) or homotetramer (20Xu J. Liu Y. Yang Y. Bates S. Zhang J.T. J. Biol. Chem. 2004; 279: 19781-19789Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). However, whether BCRP is involved in the multidrug resistance in prostate cancer remains elusive. ATP binding cassette glutathione S-transferase hemagglutinin mitoxantrone docetaxel proline-rich toptecan. To further explore the mechanisms of Pim-1L-mediated resistance to chemotherapeutic drugs in prostate cancer cells, we employed the yeast two-hybrid screening to identify cellular proteins that are associated with 44-kDa Pim-1L, and we found BCRP as one of the potential interacting partners of Pim-1L. We also showed that expression levels of Pim-1L and BCRP are up-regulated in mitoxantrone- and docetaxel-resistant prostate cancer cell lines. Pim-1L can directly interact with and phosphorylate BCRP, which promotes BCRP dimerization and ultimately its plasma membrane localization. Our data suggest that Pim-1L may protect prostate cancer cells from apoptosis, at least in part, through interacting with and phosphorylating BCRP. These findings may provide a potential therapeutic approach by disrupting Pim-1 signaling to reverse BCRP-mediated multidrug resistance. Yeast Two-hybrid ScreeningThe full-length 44-kDa human Pim-1 cDNA was amplified by PCR using kinase inactive mutant plasmid described previously (2Xie Y. Xu K. Dai B. Guo Z. Jiang T. Chen H. Qiu Y. Oncogene. 2006; 25: 70-78Crossref PubMed Scopus (101) Google Scholar) as template with high fidelity polymerase (Invitrogen) and primers 5′-CGGAATTCCTAGCCTCCTGCCCCGCGGCG-3′ and 5′-CGGAATTCCTATTTGCTGGGCCCCGGCGAC-3′. The products were digested with EcoRI and inserted into the pGBKT7 vector (Clontech). The expression library was the human HeLa cell cDNA library (Clontech). Plasmids were introduced into yeast strain Y187, and interacting proteins were double selected for growth on His/Leu/Trp-deficient plates and β-galactosidase production. DNA sequencing was obtained using an automated sequencing apparatus (Applied Biosystems). Plasmid ConstructsThe human BCRP cDNA was amplified by PCR using a BCRP construct (19Kage K. Tsukahara S. Sugiyama T. Asada S. Ishikawa E. Tsuruo T. Sugimoto Y. Int. J. Cancer. 2002; 97: 626-630Crossref PubMed Scopus (268) Google Scholar) as template and then subcloned into the HA- and Myc-tagged expression vectors respectively to generate the N-terminal tagged HA-BCRP and Myc-BCRP construct. All human Pim-1 constructs contain the N-terminal FLAG-tag and described previously (2Xie Y. Xu K. Dai B. Guo Z. Jiang T. Chen H. Qiu Y. Oncogene. 2006; 25: 70-78Crossref PubMed Scopus (101) Google Scholar). To generate the BCRP T362A or T362D mutant, the threonine residue at position 362 was mutated to alanine or aspartic acid via oligonucleotide-directed mutagenesis with the sense primers 5′-GAAGAAGATCGCAGTCTTCAAGG-3′ or 5′-GAAGAAGATCGACGTCTTCAAGG-3′, respectively and their complementary antisense primers by using the QuikChange Mutagenesis kit (Stratagene). GST-Pim-1L and GST-proline-rich region of Pim-1L (GST-PR) constructs were generated by PCR subcloning into pGEX-6P vector (Amersham Biosciences Pharmacia biotech) with the forward primer 5′-CGGAATTCCTAGCCTCCTGCCCCGCGGCG-3′ with the reverse primers 5′-CGGAATTCCTATTTGCTGGGCCCCGGCGAC-3′ and 5′-CGGAATTCCTACCCAACCTCCAGGATG-3′, respectively. GST-Pim-1S construct is described previously (21Kim O. Jiang T. Xie Y. Guo Z. Chen H. Qiu Y. Oncogene. 2004; 23: 1838-1844Crossref PubMed Scopus (68) Google Scholar). Cell and cells were by C. W. Mohler J.L. E.M. Cancer Res. 2001; 61: Google Scholar). All other cell lines used in study were from The cells were in with cells were in with cells were in with were by using or the to the proteins were and as described previously (13Jiang T. Guo Z. Dai B. Kang M. Ann D.K. Kung H.J. Qiu Y. J. Biol. Chem. 2004; 279: 50181-50189Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, W. Chen H. K. H. M. M. 2001; PubMed Scopus Google Scholar). the proteins were by glutathione at for and then with the (21Kim O. Jiang T. Xie Y. Guo Z. Chen H. Qiu Y. Oncogene. 2004; 23: 1838-1844Crossref PubMed Scopus (68) Google Scholar, J. O. Wu J. Qiu Y. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The proteins were with the of cells with the BCRP for at The were with the and then the protein were in by with and in cells were in the and was by and antibodies were to and for at The were by using protein A or protein and then the were for at with the Cell was using protein kit was as described previously J. O. Wu J. Qiu Y. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). were with of of of of of of at for and by the with The polyclonal for BCRP was by the with a 362 of BCRP, and the were using by a The polyclonal is described previously (2Xie Y. Xu K. Dai B. Guo Z. Jiang T. Chen H. Qiu Y. Oncogene. 2006; 25: 70-78Crossref PubMed Scopus (101) Google Scholar), and the monoclonal was from The Pim-1L in vitro kinase were as described previously (2Xie Y. Xu K. Dai B. Guo Z. Jiang T. Chen H. Qiu Y. Oncogene. 2006; 25: 70-78Crossref PubMed Scopus (101) Google Scholar, O. Jiang T. Xie Y. Guo Z. Chen H. Qiu Y. Oncogene. 2004; 23: 1838-1844Crossref PubMed Scopus (68) Google Scholar). the kinase GST-Pim-1L or protein was with HA-BCRP and at in kinase and for The was by the of The phosphorylation of BCRP was detected by with and cells were on with and with of cells by the the cells were in for was by the with of monoclonal for with of for at by with the and the for at The were then and with The of BCRP mutant T362A were by using an a and the of BCRP with Pim-1L was with a and resistant cell lines were from the cell by the cells in the mitoxantrone or docetaxel by The for was by cells with and or for on the cell survival for or was used as the The drug-resistant cells were selected by drug In the cells in the presence of and and were then or cells were with the the proteins or as by using the described previously (2Xie Y. Xu K. Dai B. Guo Z. Jiang T. Chen H. Qiu Y. Oncogene. 2006; 25: 70-78Crossref PubMed Scopus (101) Google Scholar, T. Guo Z. Dai B. Kang M. Ann D.K. Kung H.J. Qiu Y. J. Biol. Chem. 2004; 279: 50181-50189Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). The of human pim-1 is and BCRP is The complementary were used as the for We were to as by the expression of the fluorescent protein the cells were into the plates or docetaxel was in the The of drugs on the of cells were by the The was as the of the for the to the of cells was and by with or to the identified in our yeast two-hybrid screening using the Pim-1L mutant as two DNA for BCRP. This interaction appears to in mammalian cells BCRP was with Pim-1L but not which the N-terminal proline-rich region suggesting that BCRP to Pim-1L. The showed that BCRP was associated with GST-Pim-1L but not with or suggesting that Pim-1L is to directly interact with BCRP, and interaction both the N-terminal proline-rich region and the kinase domain of Pim-1L. We also the of BCRP and Pim-1L on the plasma membrane the interaction between endogenous BCRP and Pim-1L in a prostate cancer cell was confirmed by the shown in To whether the interaction of Pim-1L and BCRP is involved in drug we treated cells with the for BCRP, or and then their response to chemotherapeutic shown in Pim-1 or BCRP cells to and with the vector These data suggest that both Pim-1 and BCRP are for the survival of cells in response to In we two drug-resistant cell lines and from an hormone prostate cancer cell by in or two and drugs for of hormone prostate shown in both and cells demonstrated resistance to drugs including and with the cells. The expression level of BCRP and Pim-1L was also in drug-resistant cell lines with the we not an of MDR1 in resistant lines suggesting that BCRP may play a role in the drug resistance in cell lines. To further BCRP and Pim-1L to protect cells, we cells with the BCRP the Pim-1L and then their on drug cells BCRP and were to or However, overexpression of BCRP or Pim-1L in cells survival to as previously and of Pim-1L and BCRP to a in cell These data suggest that an of BCRP and Pim-1L in anti-apoptosis signaling chemotherapeutic drugs and the drug-resistant activity of BCRP be by the Pim-1L activity in cells. shown in identified Pim-1 substrates contain the of the substrates of for the threonine 362 residue of BCRP is in the suggesting that BCRP as a for Pim-1L. This is by the that the BCRP from and cells be by a of BCRP and Pim-1L in cells induced threonine phosphorylation of BCRP, and the of with alanine or the abolished threonine phosphorylation of BCRP, suggesting that may be by Pim-1L in To further phosphorylation of BCRP we a polyclonal that of BCRP shown in the BCRP by Pim-1L but not the T362A In the detected the endogenous BCRP in and cells and phosphorylation was Pim-1L was by the our in vitro kinase demonstrated that but not the mutant directly phosphorylate BCRP in vitro These data suggest that BCRP is threonine and Pim-1L may be at least in part, for phosphorylating BCRP in cells. The of both BCRP and Pim-1L for their drug resistance was further by the that the of BCRP or Pim-1L by the resensitized cells to drugs To whether phosphorylation of of BCRP is important for BCRP-mediated drug we cells with the the BCRP or the T362A mutant and then whether cells were by the overexpression of BCRP or its mutant from apoptosis induced by chemotherapeutic drugs and shown in the BCRP the survival of cells in response to but the T362A mutant to suggesting that the of is essential for the of BCRP. of BCRP and Pim-1L in cells an on cells from apoptosis, which was was mutated into In the BCRP drug-resistant activity was endogenous Pim-1L expression was by the whereas the mutant T362D of Pim-1L These suggest that the phosphorylation of BCRP induced by Pim-1L may be for its efflux activity. on the of BCRP, in the region between the ATP binding and the transmembrane To whether phosphorylation a role for BCRP membrane we cells by the the BCRP or the T362A that the BCRP and the mutant T362D were localized on plasma membrane, whereas the T362A mutant was mainly localized in The of BCRP in the by the T362A was further confirmed by It has been reported that the of BCRP on the plasma membrane a role for its drug efflux activity (19Kage K. Tsukahara S. Sugiyama T. Asada S. Ishikawa E. Tsuruo T. Sugimoto Y. Int. J. Cancer. 2002; 97: 626-630Crossref PubMed Scopus (268) Google Scholar). We the of T362A on BCRP We the BCRP with the Myc-tagged BCRP or its T362A mutant into cells. The of BCRP was by the shown in the Myc-BCRP was associated with the HA-BCRP but such interaction was by the T362A mutation. This is further corroborated by our that the formation of endogenous BCRP in cells was compromised Pim-1L expression was by the data suggest that phosphorylation of BCRP induced by Pim-1L may the of BCRP and its plasma membrane we have shown that the 44 kDa Pim-1 kinase (Pim-1L) on plasma membrane and a more prominent role the 33 kDa isoform in anti-apoptosis signaling in response to chemotherapeutic drugs in prostate cancer cells. To identify the potential we the yeast two-hybrid of the identified in our was previously reported as proteins by using the screening This that Pim-1L and may interact with a of protein partners and play in cell study on the Pim-1L interacting and signaling the mechanisms by which Pim-1L its activity. In we the that BCRP/ABCG2 is a of Pim-1L and is an important for drug resistance in prostate cancer cells. It appears to both the N-terminal proline-rich domain and the kinase domain for Pim-1L to interact with BCRP, suggesting that more one interacting may be between BCRP and Pim-1L. We also showed that phosphorylation of BCRP by Pim-1L the of BCRP and its plasma membrane localization. in vitro studies showed that BCRP may through by such not to be for BCRP to its activity U. U. T. J. Cell Sci. 2005; PubMed Scopus Google Scholar, K. H. T. I. E. A. Ishikawa T. J. Ther. 2006; Google Scholar). It remains to be phosphorylation of the interaction between BCRP or It is that phosphorylation of a of BCRP and the highly to have to be to whether it is the We previously showed that Pim-1L can interact with tyrosine kinase Etk on the plasma membrane, and Etk is to be involved in the regulation of and promotes plasma membrane of (13Jiang T. Guo Z. Dai B. Kang M. Ann D.K. Kung H.J. Qiu Y. J. Biol. Chem. 2004; 279: 50181-50189Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, J. O. Wu J. Qiu Y. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). It is that BCRP be by both kinases in a are to proteins to drug resistance. A study showed that overexpression of BCRP in breast cancer cells not resistance to J.D. Schinkel A.H. Mol. Cancer Ther. 2002; 1: 427-434Crossref PubMed Google Scholar). However, in we showed the that BCRP is involved in resistance to a in prostate cancer cells, suggesting that BCRP may be to a of substrates we previously thought on cellular It is not whether phosphorylation of BCRP induced by Pim-1L may the of the BCRP has been shown to be highly in a of prostate cancer cells. It be to whether the drug resistant lines we in study may the of cancer cells. To further whether BCRP may play a role in docetaxel resistance in human prostate we a on tissue from were treated with docetaxel for at least using our Our a of BCRP phosphorylation in the docetaxel-resistant with the suggesting that BCRP activity may to docetaxel resistance in prostate It remains to be whether the be used to in response to that of BCRP and Pim-1L expression prostate cancer cells to chemotherapeutic it is that with Pim-1 or BCRP the of for prostate cancer and the development of drug resistance. We and E. for the essential used in our

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