Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
Cell Death Dis. 2019 Jan 25;10(2):73. doi: 10.1038/s41419-019-1306-x.
Protein kinase CK2 is a highly conserved and constitutively active Ser/Thr-kinase that phosphorylates a large number of substrates, resulting in increased cell proliferation and survival. A known target of CK2 is Akt, a player in the PI3K/Akt/mTORC1 signaling pathway, which is aberrantly activated in 32% of colorectal cancer (CRC) patients. On the other hand, mTORC1 plays an important role in the regulation of protein synthesis, cell growth, and autophagy. Some studies suggest that CK2 regulates mTORC1 in several cancers. The most recently developed CK2 inhibitor, silmitasertib (formerly CX-4945), has been tested in phase I/II trials for cholangiocarcinoma and multiple myeloma. This drug has been shown to induce autophagy and enhance apoptosis in pancreatic cancer cells and to promote apoptosis in non-small cell lung cancer cells. Nevertheless, it has not been tested in studies for CRC patients. We show in this work that inhibition of CK2 with silmitasertib decreases in vitro tumorigenesis of CRC cells in response to G2/M arrest, which correlates with mTORC1 inhibition and formation of large cytoplasmic vacuoles. Notably, molecular markers indicate that these vacuoles derive from massive macropinocytosis. Altogether, these findings suggest that an aberrantly elevated expression/activity of CK2 may play a key role in CRC, promoting cell viability and proliferation in untreated cells, however, its inhibition with silmitasertib promotes methuosis-like cell death associated to massive catastrophic vacuolization, accounting for decreased tumorigenicity at later times. These characteristics of silmitasertib support a potential therapeutic use in CRC patients and probably other CK2-dependent cancers.
蛋白激酶 CK2 是一种高度保守且组成性激活的丝氨酸/苏氨酸激酶,可磷酸化大量底物,导致细胞增殖和存活增加。CK2 的一个已知靶标是 Akt,它是 PI3K/Akt/mTORC1 信号通路的参与者,在 32%的结直肠癌(CRC)患者中异常激活。另一方面,mTORC1 在调节蛋白质合成、细胞生长和自噬中发挥重要作用。一些研究表明,CK2 在几种癌症中调节 mTORC1。最近开发的 CK2 抑制剂 silmitasertib(前身为 CX-4945)已在胆管癌和多发性骨髓瘤的 I/II 期临床试验中进行了测试。该药物已被证明可诱导胰腺癌细胞自噬和增强细胞凋亡,并促进非小细胞肺癌细胞凋亡。然而,它尚未在 CRC 患者的研究中进行测试。我们在这项工作中表明,用 silmitasertib 抑制 CK2 可降低 CRC 细胞体外对 G2/M 期阻滞的致瘤性,这与 mTORC1 抑制和大细胞质空泡的形成相关。值得注意的是,分子标志物表明这些空泡源自大量巨胞饮作用。总之,这些发现表明 CK2 的异常升高表达/活性可能在 CRC 中发挥关键作用,在未处理的细胞中促进细胞活力和增殖,然而,用 silmitasertib 抑制 CK2 可促进与大量灾难性空泡化相关的类细胞死亡,这解释了后期肿瘤发生能力降低。silmitasertib 的这些特征支持其在 CRC 患者和可能其他依赖 CK2 的癌症中的潜在治疗用途。