CCL2-CCR2 轴促进卡巴他赛耐药前列腺癌细胞的迁移。

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

General Surgery, Grand Med Hospital, Ulaanbaatar, Mongolia.

Anticancer Res. 2023 Jun;43(6):2561-2569. doi: 10.21873/anticanres.16423.

BACKGROUND/AIM: Developing resistance to cabazitaxel is a major challenge in patients with docetaxel- and castration-resistant prostate cancer (CRPC) since it is frequently administered as a last resort. We have previously reported that CCL2 induces resistance to the antiproliferative effect of cabazitaxel in DU145-TxR/CxR prostate cancer cell lines. However, how CCL2 induces resistance to the antimigration effect of cabazitaxel remains unclear.

MATERIALS AND METHODS

We established a cabazitaxel-resistant cell line, DU145-TxR/CxR, from a previously established paclitaxel-resistant cell line, DU145-TxR, which was confirmed to show docetaxel resistance. We performed migration assay and analyzed the expression of epithelial-mesenchymal transition markers using DU145-TxR/CxR with or without CCL2 silencing with small interfering RNA (siRNA) transfection.

RESULTS

Cabazitaxel inhibited the migration of DU145 cells through the inactivation of STAT3. A CCR2 (a specific receptor of CCL2) antagonist suppressed the migration of DU145-TxR and DU145-TxR/CxR cells under cabazitaxel treatment. Western blotting revealed that the CCR2 antagonist inhibited STAT3 phosphorylation in DU145-TxR and DU145-TxR/CxR cells under cabazitaxel treatment. CCL2 silencing with siRNA in DU145-TxR and DU145-TxR/CxR cells decreased migration through STAT3 and p38 inactivation. Furthermore, CCL2 activated AKT, and CCR2 antagonist inhibited AKT phosphorylation in DU145-TxR and DU145-TxR/CxR cells with recovery of sensitivity to cabazitaxel under cabazitaxel treatment.

CONCLUSION

The CCL2-CCR2 axis is a key contributor to resistance to the antimigration effect of cabazitaxel in prostate cancer cells. CCL2-CCR2 axis inhibition may be a potential therapeutic target against chemoresistant CRPC in combination with cabazitaxel.

背景/目的：对于接受多西他赛和去势抵抗性前列腺癌（CRPC）治疗的患者，卡巴他赛耐药是一个主要挑战，因为它通常是作为最后的治疗手段。我们之前报道过 CCL2 可诱导 DU145-TxR/CxR 前列腺癌细胞系对卡巴他赛的增殖抑制作用产生耐药性。然而，CCL2 如何诱导对卡巴他赛的迁移抑制作用产生耐药性尚不清楚。

材料和方法

我们从先前建立的紫杉醇耐药细胞系 DU145-TxR 中建立了卡巴他赛耐药细胞系 DU145-TxR/CxR，该细胞系被证实对多西他赛耐药。我们进行了迁移实验，并使用 CCL2 沉默的小干扰 RNA（siRNA）转染分析了 DU145-TxR/CxR 中上皮-间充质转化标志物的表达。

结果

卡巴他赛通过 STAT3 的失活抑制 DU145 细胞的迁移。CCR2（CCL2 的特异性受体）拮抗剂在卡巴他赛处理下抑制 DU145-TxR 和 DU145-TxR/CxR 细胞的迁移。Western blot 分析显示，CCR2 拮抗剂在卡巴他赛处理下抑制 DU145-TxR 和 DU145-TxR/CxR 细胞中 STAT3 的磷酸化。DU145-TxR 和 DU145-TxR/CxR 细胞中 CCL2 的 siRNA 沉默通过 STAT3 和 p38 的失活降低了迁移。此外，CCL2 激活 AKT，CCR2 拮抗剂抑制 DU145-TxR 和 DU145-TxR/CxR 细胞中 AKT 的磷酸化，使细胞对卡巴他赛的敏感性恢复，在卡巴他赛处理下。