Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, China; Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, Guangdong, China.
Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.
Life Sci. 2021 Aug 15;279:119696. doi: 10.1016/j.lfs.2021.119696. Epub 2021 Jun 5.
Janus 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.
The 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 vitro and in vivo experiments 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 (IC) curves, the effect of combination therapy was confirmed.
Our 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.
Our 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.
Janus 激酶 2（JAK2）/信号转导和转录激活因子（STAT）信号在乳腺癌的进展中起着关键作用。然而，一小部分肿瘤细胞能逃过 JAK2 抑制剂的杀伤作用。我们旨在寻找乳腺癌细胞耐药的机制，并开发新的治疗策略。
用细胞计数试剂盒 8 和流式细胞术证实 TG101209 在乳腺癌细胞中的抗肿瘤作用。Western blot 用于确定 TG101209 诱导的锌指 SWIM 型包含 4（ZSWIM4）的上调。进行体外和体内实验以评估 ZSWIM4 在乳腺癌细胞对 TG101209 耐药中的作用。通过确定和分析 50%抑制浓度（IC）曲线，证实联合治疗的效果。
我们的数据表明，ZSWIM4 的表达升高有助于 JAK2 抑制耐药，因为 ZSWIM4 的敲低显著增强了乳腺癌细胞对 TG101209 的敏感性，而过表达该基因则减轻了杀伤作用。此外，ZSWIM4 敲低的乳腺癌细胞中维生素 D 受体（VDR）的表达和 1α,25-（OH）2VD3 的利用减少。VDR 沉默或 GW0742 介导的 VDR 活性阻断可部分逆转 JAK2 抑制耐药。
我们的数据表明，ZSWIM4 可能是乳腺癌细胞 JAK2 抑制的诱导耐药基因。JAK2 抑制剂和 VDR 抑制剂的联合使用可能在乳腺癌中实现更好的协同治疗效果。
