CCR1/CCL5 interaction promotes invasion of taxane-resistant PC3 prostate cancer cells by increasing secretion of MMPs 2/9 and by activating ERK and Rac signaling
CCR1/CCL5 interaction promotes invasion of taxane-resistant PC3 prostate cancer cells by increasing secretion of MMPs 2/9 and by activating ERK and Rac signaling
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DOI：
10.1016/j.cyto.2013.06.313
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发表时间：
2013-10-01
期刊：
影响因子：
3.8
通讯作者：
Ito, Masafumi
中科院分区：
文献类型：
--
作者：
Kato, Taku;Fujita, Yasunori;Ito, Masafumi
去势难治性前列腺癌（CRPC）采用紫杉烷为基础的化疗治疗，但最终会产生耐药性。因此，为CRPC患者的紫杉烷耐药寻找新的治疗靶点是必要的。我们利用由紫杉醇耐药前列腺癌细胞（PC3PR）建立的紫杉醇耐药前列腺癌细胞（PC3PR），研究趋化因子（C-C基序）受体1 （CCR1）及其配体趋化因子（C-C基序）配体5 （CCL5）在紫杉醇耐药CRPC中的作用。我们发现，与PC3细胞相比，PC3PR细胞中CCR1 mRNA和蛋白的表达水平上调。为了研究CCR1增加在PC3PR细胞中的作用，我们用CCR1的趋化因子配体之一CCL5刺激细胞。在ccl5刺激的PC3PR细胞中，sirna介导的CCR1表达下调降低了ERK1/2和Rac1/cdc42的磷酸化。此外，CCR1敲低和MEK1/2抑制降低了ccl5刺激的MMPs 2和9的分泌，而MMPs 2和9在癌细胞的侵袭和转移中起重要作用。在Matrigel侵袭实验中，敲低CCR1和抑制ERK和Rac信号通路可显著减少入侵细胞的数量。最后，ELISA检测的血清CCL5蛋白水平在前列腺活检阴性、初诊前列腺癌、紫杉烷耐药前列腺癌三组患者中均无差异。这些结果首次证明，CCR1表达增加引起的CCR1与CCL5的相互作用通过增加MMPs 2和9的分泌以及激活ERK和Rac信号传导来促进PC3PR细胞的侵袭。我们的研究结果表明，CCR1可能是紫杉烷耐药CRPC的一个新的治疗靶点。(C) 2013 Elsevier Ltd.版权所有。
Castration-refractory prostate cancer (CRPC) is treated with taxane-based chemotherapy, but eventually becomes drug resistant. It is thus essential to identify novel therapeutic targets for taxane resistance in CRPC patients. We investigated the role of the chemokine (C-C motif) receptor 1 (CCR1) and its ligand, chemokine (C-C motif) ligand 5 (CCL5), in taxane-resistant CRPC using paclitaxel-resistant prostate cancer cells (PC3PR) established from PC3 cells. We found that the expression levels of CCR1 mRNA and protein were up-regulated in PC3PR cells compared to PC3 cells. In order to investigate the role of increased CCR1 in PC3PR cells, we stimulated cells with CCL5, one of the chemokine ligands of CCR1. In CCL5-stimulated PC3PR cells, siRNA-mediated knockdown of CCR1 expression reduced phosphorylation of ERK1/2 and Rac1/cdc42. Furthermore, CCR1 knockdown and MEK1/2 inhibition decreased CCL5-stimulated secretion of MMPs 2 and 9, which play important roles in cancer cell invasion and metastasis. In the Matrigel invasion assay, knockdown of CCR1 and inhibition of the ERK and Rac signaling pathways significantly decreased the number of invading cells. Finally, the serum CCL5 protein level as measured by ELISA was not different among the three groups of patients: those with negative prostate biopsy, those at initial diagnosis of prostate cancer, and those with taxane-resistant prostate cancer. These results demonstrated for the first time that the interaction of CCR1 with CCL5 caused by increased expression of CCR1 promotes invasion of PC3PR cells by increasing secretion of MMPs 2 and 9 and by activating ERK and Rac signaling. Our findings suggest that CCR1 could be a novel therapeutic target for taxane-resistant CRPC. (C) 2013 Elsevier Ltd. All rights reserved.