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Cancer Cell Int. 2017 Mar 31;17:42. doi: 10.1186/s12935-017-0413-y. eCollection 2017.

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

Author information

1
Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Área Investigaciones, Av. San Martín 5481, Buenos Aires, Argentina.
2
CONICET, Buenos Aires, Argentina.
3
Laboratorio de Oncología Molecular, División de Productos Farmacéuticos, Centro de Genética Ingeniería y Biotecnología (CIGB), Havana, Cuba.
4
Laboratorio de Oncología Molecular, Universidad Nacional de Quilmes, Bernal, Buenos Aires, Argentina.

Abstract

BACKGROUND:

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths worldwide. Up to 80% of cancer patients are classified as non-small-cell lung cancer (NSCLC) and cisplatin remains as the 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 antitumor peptide with a novel mechanism of action, since it binds to CK2 substrates thus preventing the enzyme activity. The aim of this work was to analyze the effects of CIGB-300 treatment targeting CK2-dependent signaling pathways in NSCLC 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 through the hanging-drop method. A cisplatin resistant A549 cell line was obtained by chronic administration of cisplatin. Cell viability, 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 three-dimensional NSCLC models, presenting rapid and complete peptide uptake. This effect was accompanied by the inhibition of the CK2-dependent canonical NF-κB pathway, evidenced by reduced RelA/p65 nuclear levels and NF-κB protein targets modulation in both lung cancer cell lines, as well as conditionally reduced NF-κB transcriptional activity. 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 that NF-κB activation has been linked to cisplatin-induced resistance, we explored whether CIGB-300 could bring additional therapeutic benefits to the standard cisplatin treatment. We established a resistant cell line that showed higher p65 nuclear levels after cisplatin treatment as compared with the parental cell line. Remarkably, the cisplatin-resistant cell line became more sensitive to CIGB-300 treatment.

CONCLUSIONS:

Our data provide new insights into CIGB-300 mechanism of action and suggest clinical potential on current NSCLC therapy.

KEYWORDS:

CIGB-300; CK2; NF-κB; NSCLC

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