The 44-kDa pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells
The 44-kDa pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells
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DOI：
10.1074/jbc.m707773200
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发表时间：
2008-02-08
影响因子：
4.8
通讯作者：
Qiu, Yun
中科院分区：
文献类型：
--
作者：
Xie, Yingqiu;Xu, Kexin;Qiu, Yun
我们先前显示44-kDa丝氨酸/苏氨酸激酶Pim-1（Pim-1 L）可保护前列腺癌细胞免于化疗药物诱导的凋亡（Xie，Y.，徐，K.，Dai，B.，郭志，江，T.，Chen，H.，和Qiu，Y.（2006）Oncogene 25，70-78）。为了进一步探讨Pim-1 L介导的前列腺癌细胞对化疗药物耐药的机制，我们采用酵母双杂交筛选与Pim-1 L相关的细胞蛋白，发现ABC转运蛋白BCRP/ABCG 2是Pim-1 L的潜在相互作用伙伴之一。我们还发现，Pim-1 L和BCRP的表达水平上调米托蒽醌和紫杉醇耐药的前列腺癌细胞系。Pim-1 L与BCRP共定位于质膜上，并诱导BCRP在苏氨酸362处磷酸化。敲低Pim-1 L在耐药前列腺癌细胞中的表达，消除了内源性BCRP的多聚体形成，并使耐药细胞对化疗药物重新敏感，这表明Pim-1 L诱导的BCRP磷酸化对其功能至关重要。我们发现BCRP的质膜定位和耐药活性受到T362 A突变的损害，这进一步证实了这一点。我们的数据表明，Pim-1 L可能保护前列腺癌细胞凋亡，至少部分，通过调节跨膜药物外排泵。这些发现可能提供了一种潜在的治疗方法，通过破坏Pim-1信号传导来逆转BCRP介导的多药耐药。
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.