CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism.
CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism.
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CX-4945通过与CK2无关的机制在胆管癌细胞系中诱导甲基症。
DOI：
10.3390/cancers10090283
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发表时间：
2018-08-23
期刊：
影响因子：
5.2
通讯作者：
Satayavivad J
中科院分区：
文献类型：
--
作者：
Lertsuwan J;Lertsuwan K;Sawasdichai A;Tasnawijitwong N;Lee KY;Kitchen P;Afford S;Gaston K;Jayaraman PS;Satayavivad J
胆管细胞癌是一种预后不佳且发病率增加的疾病，因此临床上迫切需要新的辅助治疗方法。蛋白激酶CK2(以前的酪蛋白激酶II)是一种普遍表达的蛋白激酶，在多种类型的癌细胞中上调。使用CX-4945(Silmitasertib)抑制CK2活性已被建议作为一种新的治疗方法，用于包括胆管癌在内的多种疾病。在此，我们发现CX-4945在体外对胆管癌细胞系的增殖有抑制作用。此外，CX-4945处理可诱导胆管癌细胞系和其他癌细胞系形成胞浆空泡。液泡含有胞外液，pH为中性，具有甲硫磷的特征。相反，用小干扰RNA同时敲除α和α的蛋白激酶CK2催化亚基对胆管癌细胞株的增殖几乎没有影响，也不能诱导空泡的形成。令人惊讶的是，低剂量的CX-4945增加了胆管癌细胞的侵袭性，这是由于基质金属肽酶7(MMP7)的上调，而CK2的下调抑制了细胞的侵袭性。我们的数据表明，CX-4945通过CK2非依赖性途径抑制细胞增殖和诱导细胞死亡。此外，CX-4945治疗带来的细胞侵袭增加表明，该药物可能会在临床环境中增加肿瘤侵袭。
Cholangiocarcinoma is a disease with a poor prognosis and increasing incidence and hence there is a pressing unmet clinical need for new adjuvant treatments. Protein kinase CK2 (previously casein kinase II) is a ubiquitously expressed protein kinase that is up-regulated in multiple cancer cell types. The inhibition of CK2 activity using CX-4945 (Silmitasertib) has been proposed as a novel treatment in multiple disease settings including cholangiocarcinoma. Here, we show that CX-4945 inhibited the proliferation of cholangiocarcinoma cell lines in vitro. Moreover, CX-4945 treatment induced the formation of cytosolic vacuoles in cholangiocarcinoma cell lines and other cancer cell lines. The vacuoles contained extracellular fluid and had neutral pH, features characteristic of methuosis. In contrast, simultaneous knockdown of both the α and α′ catalytic subunits of protein kinase CK2 using small interfering RNA (siRNA) had little or no effect on the proliferation of cholangiocarcinoma cell lines and failed to induce the vacuole formation. Surprisingly, low doses of CX-4945 increased the invasive properties of cholangiocarcinoma cells due to an upregulation of matrix metallopeptidase 7 (MMP-7), while the knockdown of CK2 inhibited cell invasion. Our data suggest that CX-4945 inhibits cell proliferation and induces cell death via CK2-independent pathways. Moreover, the increase in cell invasion brought about by CX-4945 treatment suggests that this drug might increase tumor invasion in clinical settings.
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影响因子：
5.6
作者：
Chon HJ;Bae KJ;Lee Y;Kim J
通讯作者：
Kim J
影响因子：
4.8
作者：
Fu, Xing;Zhu, Mei-Jun;Du, Min
通讯作者：
Du, Min
影响因子：
--
作者：
Gray GK;McFarland BC;Rowse AL;Gibson SA;Benveniste EN
通讯作者：
Benveniste EN
DOI：
10.1111/j.1872-034x.2012.01030.x
发表时间：
2012-11
期刊：
Hepatology research : the official journal of the Japan Society of Hepatology
影响因子：
--
作者：
Gardner LB;Hori T;Chen F;Baine AM;Hata T;Uemoto S;Nguyen JH
通讯作者：
Nguyen JH
影响因子：
4.6
作者：
García R;Bravo E;Diez-Muñiz S;Nombela C;Rodríguez-Peña JM;Arroyo J
通讯作者：
Arroyo J