The synthetic peptide CIGB‑300 modulates CK2‑dependent signaling pathways affecting the survival and chemoresistance of non‑small cell lung cancer cell lines

CIRIGLIANO; DÍAZ BESSONE; BERARDI; FLUMIAN; BAL DE KIER JOFFÉ; PEREA; FARINA; TODARO; URTREGER

CANCER CELL INTERNATIONAL

BIOMED CENTRAL LTD

Lugar: Londres; Año: 2017 vol. 17

1475-2867

ROL PROTAGONICO EN LA AUTORIA: Background: Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deathsworldwide. Up to 80% of cancer patients are classified as non-small-cell lung cancer (NSCLC) and cisplatin remains asthe gold standard chemotherapy treatment, despite its limited efficacy due to both intrinsic and acquired resistance.The CK2 is a Ser/Thr kinase overexpressed in various types of cancer, including lung cancer. CIGB-300 is an antitumorpeptide with a novel mechanism of action, since it binds to CK2 substrates thus preventing the enzyme activity. Theaim of this work was to analyze the effects of CIGB-300 treatment targeting CK2-dependent signaling pathways inNSCLC cell lines and whether it may help improve current chemotherapy treatment.Methods: The human NSCLC cell lines NCI-H125 and NIH-A549 were used. Tumor spheroids were obtained throughthe hanging-drop method. A cisplatin resistant A549 cell line was obtained by chronic administration of cisplatin. Cellviability, apoptosis, immunoblotting, immunofluorescence and luciferase reporter assays were used to assess CIGB-300 effects. A luminescent assay was used to monitor proteasome activity.Results: We demonstrated that CIGB-300 induces an anti-proliferative response both in monolayer- and threedimensionalNSCLC models, presenting rapid and complete peptide uptake. This effect was accompanied by theinhibition of the CK2-dependent canonical NF-κB pathway, evidenced by reduced RelA/p65 nuclear levels and NF-κBprotein targets modulation in both lung cancer cell lines, as well as conditionally reduced NF-κB transcriptionalactivity. In addition, NF-κB modulation was associated with enhanced proteasome activity, possibly through its α7/C8 subunit. Neither the peptide nor a classical CK2 inhibitor affected cytoplasmic β-CATENIN basal levels. Given thatNF-κB activation has been linked to cisplatin-induced resistance, we explored whether CIGB-300 could bring additionaltherapeutic benefits to the standard cisplatin treatment. We established a resistant cell line that showed higherp65 nuclear levels after cisplatin treatment as compared with the parental cell line. Remarkably, the cisplatin-resistantcell line became more sensitive to CIGB-300 treatment.Conclusions: Our data provide new insights into CIGB-300 mechanism of action and suggest clinical potential oncurrent NSCLC therapy