Hematology Unit, Department of Medicine (DIMED), University of Padova, Padova, Italy.
Surgical Pathology and Cytopathology Unit, Department of Medicine, University of Padova, Padova, Italy.
Front Immunol. 2024 May 14;15:1393485. doi: 10.3389/fimmu.2024.1393485. eCollection 2024.
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.
Biochemical analyses and 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.
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.
在经典霍奇金淋巴瘤（cHL）中，肿瘤细胞的存活是由 NF-κB、JAK/STAT 和 PI3K/Akt 信号通路的激活介导的。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，它参与了几个细胞过程，两个亚基在实体瘤和血液恶性肿瘤中均过度表达。
生化分析和测定显示，cHL 中 CK2 亚基的表达受损，CK2α 过度表达，而 CK2β 的表达与正常 B 淋巴细胞相比则降低。从机制上讲，在所有 HL 细胞系中均发现 CK2β 被泛素化，随后被蛋白酶体途径降解。此外，在基础条件下，STAT3、NF-kB 和 AKT 在 CK2 相关靶点中被磷酸化，导致组成性通路的激活。用 CX-4945/silmitasertib 抑制 CK2 可触发 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，MMAE 是 brentuximab vedotin 的微管抑制剂。
我们的数据指出 CK2 在 cHL 中关键信号通路的存活和激活中起着关键作用。CK2α 和 CK2β 之间的倾斜表达从未在其他淋巴瘤中报道过，可能是 cHL 所特有的。CK2 抑制对 PD-L1 表达的影响以及 CX-4945/silmitasertib 与 MMAE 的协同组合表明 CK2 是开发 cHL 新疗法的高影响靶点。
