PMID: 18056989    RLIMS-P  3 eFIP  0 miRTex  0 eGARD  0  Issue Report


Title
1.The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells.
Abstract
2.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).
3.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.
4.We also showed that the expression level of Pim-1L and BCRP was up-regulated in mitoxantrone and docetaxel-resistant prostate cancer cell lines.
5.Pim-1L was co-localized with BCRP on the plasma membrane and induced phosphorylation of BCRP at threonine 362.
6.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.
7.This is further corroborated by our finding that the plasma membrane localization and drug-resistant activity of BCRP were compromised by T362A mutation.
8.Our data suggest that Pim-1L may protect prostate cancer cells from apoptosis, at least in part, through regulation of transmembrane drug efflux pump.
9.These findings may provide a potential therapeutic approach by disrupting Pim-1 signaling to reverse BCRP-mediated multidrug resistance.
Loading...

Loading data

Legend:   SUBSTRATE  KINASE  INTERACTANT  SITE  GENE  MIRNA  ANOMALY  EXPRESSION  DISEASE  OUTCOME/RESPONSE  SR_DRUG  DRUG  CELL  TRIGGER  Normalized

Tool: RLIMS-P

PTM enzymeSubstrateSiteSentence
BCRP (Q9UNQ0)6
BCRP (Q9UNQ0)Thr-3625
44-kDa Pim-1 kinaseBCRP/ABCG2 (Q9UNQ0)1