The CK2 inhibitor CX4945 reverses cisplatin resistance in the A549/DDP human lung adenocarcinoma cell line

Abstract

Lung cancer negatively impacts global health, and the incidence of non-small cell lung cancer (NSCLC) is highest among all forms of lung cancer. Chemotherapy failure mainly occurs due to drug resistance; however, the associated molecular mechanism remains unclear. Casein kinase II (CK2), which plays important roles in the occurrence, development and metastasis of many tumours, regulates Wnt signaling by modulating β-catenin expression. In the present study the effects of the CK2 inhibitor, CX4945 on cisplatin [or cis-diamminedichloroplatinum (II); (DDP)]-resistant A549 cells (A549/DDP) were investigated to elucidate the underlying molecular mechanism. A549/DDP cells were divided into four groups (blank control, CX4945, cisplatin and CX4945+cisplatin). Cisplatin resistance was 5.16-fold greater in A549/DDP cells compared with that in A549 cells, with an optimal cisplatin concentration of 5 µg/ml. Moreover, levels of CK2, dishevelled-2 (DVL-2) phosphorylated (p) at Ser143 (p-DVL-2 Ser143), and major Wnt-signaling proteins were significantly higher in A549/DDP cells compared with that in A549 cells (P<0.05), with these levels further increased following cisplatin treatment (P<0.05), whereas these levels significantly decreased in A549 cells after cisplatin treatment (P<0.05). Additionally, multidrug-resistance-associated protein 1 and lung resistance protein expression was significantly higher in A549/DDP cells compared with that in A549 cells (P<0.05), with these levels increasing further in A549/DDP (P<0.05) but not A549 cells upon cisplatin treatment (P>0.05). In addition, reduced expression of resistance proteins in A549/DDP cells was accompanied by a decline in the 50% growth inhibition after CX4945 pre-treatment. Furthermore, levels of p-DVL-2 Ser143 and major Wnt-signaling proteins decreased significantly after treatment of A549/DDP cells with CX4945+cisplatin, whereas DVL-2 and p-DVL-2 Thr224 levels remained unchanged. Additionally, significant elevations in apoptosis rates in the CX4945+cisplatin group relative to the control and cisplatin-only groups, was observed (P<0.001). These results suggested that inhibiting Wnt/β-catenin signaling with CX4945, which attenuates levels of drug-resistanceassociated proteins and induces apoptosis, might reverse cisplatin resistance in NSCLC.

Etil Piruvatın Çeşitli Kanser Hücre Hatları Üzerindeki Sitotoksik Etkisinin İncelenmesi

“…When Table 1 is examined, it is seen that IC50 values for CDDP ranged from 2.06 to 9.14 µM in cancer cell lines. Consistent with these results, it is reported that the IC50 values of CDDP on HeLa and A549 cell lines vary between 0.75 to 8.6 µM (Gumus et al, 2009;Casagrande et al, 2013;Singh et al, 2015) and 1.12 to 7 µM (Adach et al, 2016;Jin et al, 2019;Zhang et al, 2020), respectively. Similarly, it is reported that the IC50 values of CDDP on MCF-7 and HepG2 cell lines vary between 3.09 to 12.5 µM (Aung et al, 2007;Gumus et al, 2009;Mansouri-Torshizi et al, 2016) and 7.75 to 24.1 µM (Sakinah et al, 2007;Adach et al, 2016;Hashiesh et al, 2018), respectively.…”

Phosphoproteomic Landscape of AML Cells Treated with the ATP-Competitive CK2 Inhibitor CX-4945

“…Therefore, down-phosphorylation of these candidate substrates could modulate the Wnt signaling pathway. Supporting this hypothesis, previous studies highlights that CK2 is a positive regulator of Wnt signaling pathway and CK2 inhibition by CX-4945 has been associated with Wnt/β-catenin inhibition [ 75 , 76 ].…”

CX-4945 and siRNA-Mediated Knockdown of CK2 Improves Cisplatin Response in HPV(+) and HPV(−) HNSCC Cell Lines

“…We have previously shown in prostate cancer that CK2 inhibition has a negative impact on mitochondrial health through decreased membrane potential and Ca 2+ flux [ 27 , 46 ]. CK2 has significant influence on numerous DNA repair and other pathways activated by radiation and cisplatin [ 27 , 47 , 48 , 49 ]; loss of CK2 improves sensitivity to cisplatin or radiation in numerous cancers, including head and neck cancer [ 42 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. CX-4945 blocks DNA repair after cisplatin or gemcitabine treatment [ 51 , 63 ], and next generation platinum Pt(IV) prodrugs conjugated with CX-4945 have shown efficacy in other cancer types [ 64 ].…”