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Abstract：
UNASSIGNED: In classical Hodgkin lymphoma (cHL), the survival of neoplastic cells is mediated by the activation of NF-κB, JAK/STAT and PI3K/Akt signaling pathways. CK2 is a highly conserved serine/threonine kinase, consisting of two catalytic (α) and two regulatory (β) subunits, which is involved in several cellular processes and both subunits were found overexpressed in solid tumors and hematologic malignancies.
UNASSIGNED: Biochemical analyses and in vitro assays showed an impaired expression of CK2 subunits in cHL, with CK2α being overexpressed and a decreased expression of CK2β compared to normal B lymphocytes. Mechanistically, CK2β was found to be ubiquitinated in all HL cell lines and consequently degraded by the proteasome pathway. Furthermore, at basal condition STAT3, NF-kB and AKT are phosphorylated in CK2-related targets, resulting in constitutive pathways activation. The inhibition of CK2 with CX-4945/silmitasertib triggered the de-phosphorylation of NF-κB-S529, STAT3-S727, AKT-S129 and -S473, leading to cHL cell lines apoptosis. Moreover, CX-4945/silmitasertib was able to decrease the expression of the immuno-checkpoint CD274/PD-L1 but not of CD30, and to synergize with monomethyl auristatin E (MMAE), the microtubule inhibitor of brentuximab vedotin.
UNASSIGNED: Our data point out a pivotal role of CK2 in the survival and the activation of key signaling pathways in cHL. The skewed expression between CK2α and CK2β has never been reported in other lymphomas and might be specific for cHL. The effects of CK2 inhibition on PD-L1 expression and the synergistic combination of CX-4945/silmitasertib with MMAE pinpoints CK2 as a high-impact target for the development of new therapies for cHL.
UNASSIGNED: Biochemical analyses and in vitro assays showed an impaired expression of CK2 subunits in cHL, with CK2α being overexpressed and a decreased expression of CK2β compared to normal B lymphocytes. Mechanistically, CK2β was found to be ubiquitinated in all HL cell lines and consequently degraded by the proteasome pathway. Furthermore, at basal condition STAT3, NF-kB and AKT are phosphorylated in CK2-related targets, resulting in constitutive pathways activation. The inhibition of CK2 with CX-4945/silmitasertib triggered the de-phosphorylation of NF-κB-S529, STAT3-S727, AKT-S129 and -S473, leading to cHL cell lines apoptosis. Moreover, CX-4945/silmitasertib was able to decrease the expression of the immuno-checkpoint CD274/PD-L1 but not of CD30, and to synergize with monomethyl auristatin E (MMAE), the microtubule inhibitor of brentuximab vedotin.
UNASSIGNED: Our data point out a pivotal role of CK2 in the survival and the activation of key signaling pathways in cHL. The skewed expression between CK2α and CK2β has never been reported in other lymphomas and might be specific for cHL. The effects of CK2 inhibition on PD-L1 expression and the synergistic combination of CX-4945/silmitasertib with MMAE pinpoints CK2 as a high-impact target for the development of new therapies for cHL.
摘要：
■在经典霍奇金淋巴瘤（cHL）中，肿瘤细胞的存活是由NF-κB的激活介导的，JAK/STAT和PI3K/Akt信号通路。CK2是一种高度保守的丝氨酸/苏氨酸激酶，由两个催化（α）和两个调节（β）亚基组成，它参与了多个细胞过程，并且发现两个亚基在实体瘤和血液系统恶性肿瘤中过度表达。
■生化分析和体外分析显示cHL中CK2亚基的表达受损，与正常B淋巴细胞相比，CK2α过表达且CK2β表达降低。机械上,发现CK2β在所有HL细胞系中被泛素化，因此被蛋白酶体途径降解。此外，在基础条件下，STAT3，NF-kB和AKT在CK2相关靶标中磷酸化，导致组成途径激活。用CX-4945/silmitasertib抑制CK2触发NF-κB-S529，STAT3-S727，AKT-S129和-S473的去磷酸化，导致cHL细胞系凋亡。此外，CX-4945/silmitasertib能够降低免疫检查点CD274/PD-L1的表达，但不降低CD30的表达，并与单甲基奥瑞他汀E（MMAE）协同作用，本妥昔单抗vedotin的微管抑制剂。
■我们的数据指出了CK2在cHL的存活和关键信号通路的激活中的关键作用。在其他淋巴瘤中从未报道过CK2α和CK2β之间的偏斜表达，并且可能对cHL具有特异性。CK2抑制对PD-L1表达的影响以及CX-4945/silmitasertib与MMAE的协同组合确定了CK2作为开发cHL新疗法的高影响靶标。
■生化分析和体外分析显示cHL中CK2亚基的表达受损，与正常B淋巴细胞相比，CK2α过表达且CK2β表达降低。机械上,发现CK2β在所有HL细胞系中被泛素化，因此被蛋白酶体途径降解。此外，在基础条件下，STAT3，NF-kB和AKT在CK2相关靶标中磷酸化，导致组成途径激活。用CX-4945/silmitasertib抑制CK2触发NF-κB-S529，STAT3-S727，AKT-S129和-S473的去磷酸化，导致cHL细胞系凋亡。此外，CX-4945/silmitasertib能够降低免疫检查点CD274/PD-L1的表达，但不降低CD30的表达，并与单甲基奥瑞他汀E（MMAE）协同作用，本妥昔单抗vedotin的微管抑制剂。
■我们的数据指出了CK2在cHL的存活和关键信号通路的激活中的关键作用。在其他淋巴瘤中从未报道过CK2α和CK2β之间的偏斜表达，并且可能对cHL具有特异性。CK2抑制对PD-L1表达的影响以及CX-4945/silmitasertib与MMAE的协同组合确定了CK2作为开发cHL新疗法的高影响靶标。
