Anti-Growth, Anti-Angiogenic, and Pro-Apoptotic Effects by CX-4945, an Inhibitor of Casein Kinase 2, on HuCCT-1 Human Cholangiocarcinoma Cells via Control of Caspase-9/3, DR-4, STAT-3/STAT-5, Mcl-1, eIF-2α, and HIF-1α.
Anti-Growth, Anti-Angiogenic, and Pro-Apoptotic Effects by CX-4945, an Inhibitor of Casein Kinase 2, on HuCCT-1 Human Cholangiocarcinoma Cells via Control of Caspase-9/3, DR-4, STAT-3/STAT-5, Mcl-1, eIF-2α, and HIF-1α.
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酪蛋白激酶2抑制剂CX-4945通过调控Caspase-9/3、DR-4、STAT-3/STAT-5、Mcl-1、eIF-2α和HIF-1α抑制HuCCT-1人胆管癌细胞的生长、抗血管生成和促凋亡作用。
DOI：
10.3390/ijms23116353
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发表时间：
2022-06-06
影响因子：
5.6
通讯作者：
Jang, Byeong-Churl
中科院分区：
文献类型：
--
作者：
Wang, Saini;Yadav, Anil Kumar;Han, Jin-Yi;Ahn, Keun Soo;Jang, Byeong-Churl
酪蛋白激酶2（CK 2）的过表达在许多癌症中具有致癌和促生存作用。CX-4945（Silmitasertib）是一种CK 2抑制剂，具有抗癌和抗血管生成作用。目前，CX-4945对人胆管癌（CCA）的抗癌作用及其机制尚不清楚。本研究调查了CX-4945是否抑制HuCCT-1细胞（一种人CCA细胞系）的生长并诱导其凋亡。值得注意的是，用20 μM CX-4945处理显著降低了HuCCT-1细胞的存活率并诱导了细胞凋亡，如核DNA片段化、PARP切割、半胱天冬酶-9/3活化和DR-4上调所证明。虽然CX-4945不影响CK 2的磷酸化和表达，但它极大地抑制了CK 2底物的磷酸化，支持了该药物抑制CK 2及其下游途径的功效。重要的是，部分抑制CK 2底物磷酸化的CK 2敲低导致HuCCT-1细胞存活率显著降低。此外，CX-4945降低了HuCCT-1细胞中STAT-3和STAT-5的磷酸化和表达，这些蛋白质的药理学抑制或各自的敲低导致HuCCT-1细胞的显著生长抑制。CX-4945还能够降低HuCCT-1细胞中Mcl-1的表达，同时增加eIF-2α的磷酸化。CX-4945对HuCCT-1细胞中HIF-1α的表达具有时间差异性的负调控作用，下调HIF-1α的表达可显著降低细胞存活率。总之，这些结果表明CX-4945对HuCCT-1细胞具有抗生长、抗血管生成和促凋亡作用，其通过控制CK 2、caspase-9/3、DR-4、STAT-3/5、Mcl-1、eIF-2α和HIF-1α介导。
Overexpression of casein kinase 2 (CK2) has an oncogenic and pro-survival role in many cancers. CX-4945 (Silmitasertib) is a CK2 inhibitor with anti-cancerous and anti-angiogenic effects. Up to date, the anti-cancer effect and mechanism of CX-4945 on human cholangiocarcinoma (CCA) remain unclear. This study investigated whether CX-4945 inhibits growth and induces apoptosis of HuCCT-1 cells, a human CCA cell line. Of note, treatment with CX-4945 at 20 μM markedly reduced survival and induced apoptosis of HuCCT-1 cells, as evidenced by nuclear DNA fragmentation, PARP cleavage, activation of caspase-9/3, and up-regulation of DR-4. Although CX-4945 did not affect the phosphorylation and expression of CK2, it vastly inhibited the phosphorylation of CK2 substrates, supporting the drug’s efficacy in inhibiting CK2 and its downstream pathway. Importantly, knockdown of CK2 that partially suppressed the phosphorylation of CK2 substrates resulted in a significant reduction of HuCCT-1 cell survival. In addition, CX-4945 reduced the phosphorylation and expression of STAT-3 and STAT-5 in HuCCT-1 cells, and pharmacological inhibition or respective knockdown of these proteins resulted in significant growth suppression of HuCCT-1 cells. CX-4945 also had abilities to decrease Mcl-1 expression while increasing eIF-2α phosphorylation in HuCCT-1 cells. Furthermore, there was a time-differential negative regulation of HIF-1α expression by CX-4945 in HuCCT-1 cells, and knockdown of HIF-1α caused a significant reduction of the cell survival. In summary, these results demonstrated that CX-4945 has anti-growth, anti-angiogenic, and pro-apoptotic effects on HuCCT-1 cells, which are mediated through control of CK2, caspase-9/3, DR-4, STAT-3/5, Mcl-1, eIF-2α, and HIF-1α.
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