SWIM domain protein ZSWIM4 is required for JAK2 inhibition resistance in breast cancer
SWIM domain protein ZSWIM4 is required for JAK2 inhibition resistance in breast cancer
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SWIM 结构域蛋白 ZSWIM4 是乳腺癌 JAK2 抑制抵抗所必需的
DOI：
10.1016/j.lfs.2021.119696
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发表时间：
2021-06-08
期刊：
影响因子：
6.1
通讯作者：
Shi，Jian
中科院分区：
文献类型：
--
作者：
Gong，Kunxiang;Song，Kai;Shi，Jian
Janus激酶2（JAK 2）/信号转导和转录激活因子（STAT）信号转导在乳腺癌的发生发展中起着重要作用。然而，一小部分肿瘤细胞因JAK 2抑制剂的杀伤作用而存活。我们的目的是找出乳腺癌细胞的耐药机制，并制定新的治疗策略。材料和方法TG 101209对乳腺癌细胞的抗肿瘤作用通过细胞计数试剂盒8和流式细胞术证实。Western blotting检测TG 101209对SWIM-type containing 4（SWIM 4）表达的影响;体外和体内实验检测SWIM 4在乳腺癌细胞对TG 101209耐药中的作用。通过50%抑制浓度（IC 50）曲线的测定和分析，证实了联合治疗的效果。关键发现我们的数据表明，JAKWIM 4的高表达有助于JAK 2抑制抗性，因为JAKWIM 4的敲低显著增强了乳腺癌细胞对TG 101209的敏感性，而该基因的过表达减轻了杀伤作用。此外，维生素D受体（VDR）的表达和1α，25-（OH）2 VD 3的利用在WIM 4敲低的乳腺癌细胞中降低。VDR沉默或GW 0742介导的VDR活性阻断可部分逆转乳腺癌细胞对JAK 2抑制的抗性。JAK 2抑制剂与VDR抑制剂联合应用对乳腺癌的协同治疗效果更佳。
AimsJanus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) signaling plays a critical role in the progression of breast cancer. However, a small part of tumor cells survived from the killing effect of JAK2 inhibitor. We aimed to find out the mechanism of drug resistance in breast cancer cells and develop new therapeutic strategies.Materials and methodsThe anti-tumor effect of TG101209 in breast cancer cells was confirmed by cell counting kit 8 and flow cytometry. Western blotting was used to determine the up-regulation of zinc finger SWIM-type containing 4 (ZSWIM4) induced by TG101209.In vitroandin vivoexperiments were performed to evaluate the role of ZSWIM4 in the resistance of breast cancer cells to TG101209. Through the determination and analysis of 50% inhibiting concentration (IC50) curves, the effect of combination therapy was confirmed.Key findingsOur data indicate that the elevated expression of ZSWIM4 contributes to JAK2 inhibition resistance, as knockdown of ZSWIM4 significantly enhances the sensitivity of breast cancer cells to TG101209 and over-expression of this gene mitigates the killing effect. Furthermore, the expression of vitamin D receptor (VDR) and utilization of 1α,25-(OH)2VD3 is decreased in ZSWIM4-knockdown breast cancer cells. VDR-silencing or GW0742-mediated blockade of VDR activity can partially reverse the JAK2 inhibition resistance.SignificanceOur data implicated that ZSWIM4 might be an inducible resistance gene of JAK2 inhibition in breast cancer cells. The combination of JAK2 inhibitor and VDR inhibitor may achieve better coordinated therapeutic effect in breast cancer.