Establishment and characterization of two cabazitaxel-resistant prostate cancer cell lines.
Establishment and characterization of two cabazitaxel-resistant prostate cancer cell lines.
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DOI：
10.18632/oncotarget.24609
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发表时间：
2018-03-23
期刊：
影响因子：
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通讯作者：
Mizokami A
中科院分区：
文献类型：
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作者：
Machioka K;Izumi K;Kadono Y;Iwamoto H;Naito R;Makino T;Kadomoto S;Natsagdorj A;Keller ET;Zhang J;Mizokami A
一旦去势抵抗性前列腺癌（CRPC）对卡巴他赛治疗产生耐药性，患者就必须接受最佳支持治疗。因此，阐明并攻克卡巴他赛耐药机制是改善患者预后的重要课题。然后我们尝试建立卡巴他赛耐药的 CRPC 细胞系并对其进行表征。我们从之前建立的 PC-3-TxR 和 DU145-TxR 细胞系中建立了两种卡巴他赛抗性细胞系：PC-3-TxR/CxR 和 DU145-TxR/CxR。 PC-3-TxR/CxR 和 DU145-TxR/CxR 细胞对卡巴他赛的耐药性分别提高了 11.8 倍和 4.4 倍。使用 SCID 小鼠体内 TxR/CxR 细胞显示出卡巴他赛耐药性。尽管与DU145细胞相比，DU145-TxR中多药耐药基因1（MDR1）的表达上调，但在DU145-TxR/CxR细胞中不再上调。相反，与PC-3细胞相比，PC-3-TxR中MDR1基因的表达上调，并且与PC-3-TxR细胞相比，PC-3-TxR/CxR中MDR1基因的表达进一步上调。 PC-3-TxR和PC-3-TxR/CxR细胞之间或DU145-TxR和DU145-TxR/CxR细胞之间的cDNA微阵列比较显示许多基因上调或下调。最后，MDR1 的敲低不仅在 PC-3-TxR/CxR 细胞中恢复了对卡巴他赛的敏感性，而且在 DU145-TxR/CxR 细胞中也恢复了对卡巴他赛的敏感性。总之，MDR1 基因的调节对于克服卡巴他赛耐药性非常重要。
Once castration-resistant prostate cancer (CRPC) become resistant for cabazitaxel treatment, the patients are obliged to best supportive care. Therefore, the elucidation of the mechanism of the cabazitaxel-resistance and the conquest are important themes to improve the prognosis of the patients. Then we tried to establish cabazitaxel-resistant CRPC cell lines and characterized them. We established two cabazitaxel-resistant cell lines, PC-3-TxR/CxR and DU145-TxR/CxR from PC-3-TxR and DU145-TxR cell lines previously we established. PC-3-TxR/CxR and DU145-TxR/CxR cells became resistant for cabazitaxel by 11.8-fold and 4.4-fold, respectively. The TxR/CxR cells showed cabazitaxel-resistant using SCID mice in vivo. Although expression of multi-drug resistance gene 1 (MDR1) was up-regulated in DU145-TxR compared with DU145 cells, it was not up-regulated in DU145-TxR/CxR cells any more. In contrast, expression of MDR1 gene was up-regulated in PC-3-TxR compared with PC-3 cells and it was further up-regulated in PC-3-TxR/CxR compared with PC-3-TxR cells. Comparison of cDNA microarray between PC-3-TxR and PC-3-TxR/CxR cells or between DU145-TxR and DU145-TxR/CxR cells revealed that many genes were up-regulated or down-regulated. Finally, knockdown of MDR1 recovered the sensitivity to cabazitaxel not only in PC-3-TxR/CxR cells but also DU145-TxR/CxR cells. Together, regulation of MDR1 gene is important for conquest of the cabazitaxel-resistance.